Analysis Of Patient-reported Outcomes Research Articles

Comparison of statistical methods for the analysis of patient-reported outcomes in randomised controlled trials: A simulation study.

Patient-reported outcomes(PROs) that aim to measure patients' subjective attitudes towards their health or health-related conditions in various fields have been increasingly used in randomised controlled trials(RCTs). PRO data is likely to be bounded, discrete, and skewed. Although various statistical methods are available for the analysis of PROs in RCT settings, there is no consensus on what statistical methods are the most appropriate for use. This study aims to use simulation methods to compare the performance (in terms of bias, empirical standard error, coverage of the confidence interval, Type I error, and power) of three different statistical methods, multiple linear regression(MLR), Tobit regression (Tobit), and median regression (Median), to estimate a range of predefined treatment effects for a PRO in a two-arm balanced RCT. We assumed there was an underlying latent continuous outcome that the PRO was measuring, but the actual scores observed were equally spaced and discrete. This study found that MLR was associated with little bias of the estimated treatment effect, small standard errors, and appropriate coverage of the confidence interval under most scenarios. Tobit performed worse than MLR for analysing PROs with a small number of levels, but it had better performance when analysing PROs with more discrete values. Median showed extremely large bias and errors, associated with low power and coverage for most scenarios especially when the number of possible discrete values was small. We recommend MLR as a simple and universal statistical method for the analysis of PROs inRCT settings.

Patient-Reported Outcomes of Postoperative NSCLC Patients with or without Staged Chinese Herb Medicine Therapy during Adjuvant Chemotherapy (NALLC 2): A Randomized, Double-Blind, Placebo-Controlled Trial.

To investigate whether the combination of chemotherapy with staged Chinese herbal medicine (CHM) therapy could enhance health-related quality of life (QoL) in non-small-cell lung cancer (NSCLC) patients and prolong the time before deterioration of lung cancer symptoms, in comparison to chemotherapy alone. A prospective, double-blind, randomized, controlled trial was conducted from December 14, 2017 to August 28, 2020. A total of 180 patients with stage I B-IIIA NSCLC from 5 hospitals in Shanghai were randomly divided into chemotherapy combined with CHM (chemo+CHM) group (120 cases) or chemotherapy combined with placebo (chemo+placebo) group (60 cases) using stratified blocking randomization. The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life-Core 30 Scale (QLQ-C30) was used to evaluate the patient-reported outcomes (PROs) during postoperative adjuvant chemotherapy in patients with early-stage NSCLC. Adverse events (AEs) were assessed in the safety analysis. Out of the total 180 patients, 173 patients (116 in the chemo+CHM group and 57 in the chemo+placebo group) were included in the PRO analyses. The initial mean QLQ-C30 Global Health Status (GHS)/QoL scores at baseline were 57.16 ± 1.64 and 57.67 ± 2.25 for the two respective groups (P>0.05). Compared with baseline, the chemo+CHM group had an improvement in EORTC QLQ-C30 GHS/QoL score at week 18 [least squares mean (LSM) change 17.83, 95% confidence interval (CI) 14.29 to 21.38]. Conversely, the chemo+placebo group had a decrease in the score (LSM change -13.67, 95% CI -22.70 to -4.63). A significant between-group difference in the LSM GHS/QoL score was observed, amounting to 31.63 points (95% CI 25.61 to 37.64, P<0.001). The similar trends were observed in physical functioning, fatigue and appetite loss. At week 18, patients in the chemo+CHM group had a higher proportion of improvement or stabilization in GHS/QoL functional and symptom scores compared to chemo+placebo group (P<0.001). The median time to deterioration was longer in the chemo+CHM group for GHS/QoL score [hazard ratio (HR)=0.33, 95% CI 0.23 to 0.48, P<0.0010], physical functioning (HR=0.43, 95% CI 0.25 to 0.75, P=0.0005), fatigue (HR=0.47, 95% CI 0.30 to 0.72, P<0.0001) and appetite loss (HR=0.65, 95% CI 0.42 to 1.00, P=0.0215). The incidence of AEs was lower in the chemo+CHM group than in the chemo+placebo group (9.83% vs. 15.79%, P=0.52). The staged CHM therapy could help improve the PROs of postoperative patients with early-stage NSCLC during adjuvant chemotherapy, which is worthy of further clinical research. (Registry No. NCT03372694).

Patients With Dysplasia Achieve Similar Outcomes and Survivorship to Nondysplastic Patients 10 Years After Hip Arthroscopy for Femoroacetabular Impingement

To determine the long-term outcomes of hip arthroscopy (HA) for femoroacetabular impingement (FAI) in the presence of concomitant lateral rim dysplasia compared with a matched control group. Patients undergoing HA between January 2009 and October 2013 with minimum 10-year follow-up were reviewed. The inclusion criteria consisted of patients undergoing HA for FAI with evidence of lateral rim dysplasia (lateral-center edge angle [LCEA] < 25°). Patients with lateral rim dysplasia were matched to patients with an LCEA greater than 30° based on sex, Tönnis grade, and age. Outcomes included survival (avoidance of total hip replacement [THR]), repeated HA, and patient-reported outcomes (PROs). Survivorship was assessed using a Kaplan-Meier curve and log rank test, whereas revision rates between groups were assessed using χ2 analysis. Between- and within-group analyses of PROs were conducted using the Mann-Whitney U test and Wilcoxon signed rank test, respectively. The proportion of cases achieving the patient acceptable symptom state was compared between groups using χ2 analysis. This study comprised 46 dysplasia cases and 90 control cases. There was no statistically significant difference between groups in baseline metrics apart from the LCEA (P < .001), Sharp angle (P < .001), and Tönnis angle (P < .001). By 10 years postoperatively, 9% of dysplasia cases and 4% of control cases underwent conversion to THR. There was no statistically significant difference between groups in survival or revision rates. Both groups reported improvements in PROs, and there was no difference between PRO scores at either time point. Excluding cases that underwent THR, 84% and 83% of dysplasia and control cases, respectively, achieved the patient acceptable symptom state. HA for symptomatic FAI is a successful treatment in cases in which dysplasia is present. Low complication rates, comparable outcomes to cases without lateral rim dysplasia, and a high survivorship rate of 91% at minimum 10-year follow-up are observed. Increasing Tönnis angle preoperatively may increase the risk of THR conversion. Level IV, retrospective cohort study.

Clinical outcomes following transtibial medial meniscal root repair are maintained at long-term follow-up.

To evaluate long-term outcomes of patients treated with posterior medial meniscal root tear (PMMRT) repair through assessment of functional outcome scores and to identify patient surgical and magnetic resonance imaging (MRI) characteristics associated with improved outcomes. This was a single-centre, retrospective study evaluating patients who had undergone a PMMR repair using a transtibial suture pullout technique with two locking cinch sutures. This was performed as a follow-up to previously published 2-year and 5-year outcome studies, using the same cohort. All patients from the prior short-term and midterm studies were invited to participate. Patient-reported outcome (PROs) scores, including the International Knee Documentation Committee (IKDC) and Lysholm scores, were collected. Previously collected demographic data were updated based on review of the electronic medical record. Patient outcomes were assessed preoperatively, as well as at 2-year, 5-yearand 8-yearpostoperatively. MRI outcome measurements were assessed at 2-year and 5-year follow-ups. All statistical analysis was performed using SPSS version 26. Seventeen patients of the original 18 patients (94.4%) were included in the final analysis. Additionally, three patients who had additional ipsilateral surgery were excluded from the analysis of PROs. The IKDC score significantly increased from 44.7 ± 11.6 at preoperative baseline to 71.2 ± 21.3 at 8-yearpost-operation (p = 0.001). There were no significant differences in IKDC score between 2-year and 8-year follow-ups (p = n.s.) or 5-year and 8-year follow-ups (p = n.s.). The Lysholm score significantly increased from 49.6 ± 7.3 at preoperative baseline to 76.4 ± 17.2 at 8-year follow-up (p < 0.001). There was no significant difference in Lysholm scores between 2-year and 8-year follow-ups (p = n.s.) or 5-year and 8-year follow-ups (p = n.s.). A linear regression analysis found that 5-year IKDC scores were significantly correlated with 8-year IKDC scores (β = 0.681, p = 0.038). At 8-year follow-up, four (23.5%) patients required additional procedures on their operative knee (one total knee arthroplasty conversion). Patients treated with repair of PMMRT had maintenance of clinical outcome improvements at long-term follow-up despite worsening MRI outcomes at short-term and medium-term follow-ups. While a high proportion of patients required additional procedures on their operative knee at 8-yearfollow-up, few of these patient's additional procedures were related to failure of their primary surgery. Providers and patients may expect durable clinical outcomes following the repair of PMMRT, irrespective of radiographic appearance. Level IV.

A descriptive patient-reported outcomes (PROs) analysis of KEYNOTE-412 to understand head and neck symptom burden.

11116 Background: The randomized, double-blind, phase 3 KEYNOTE-412 study (NCT03040999) investigated pembrolizumab (pembro) + chemoradiation therapy (CRT) versus placebo + CRT for locally advanced head and neck squamous cell carcinoma (LA HNSCC). Descriptive PRO analysis may provide important insight to better understand patient (pt) experiences. This analysis evaluated pt experience by examining item-level PRO scores. Methods: Adults with LA HNSCC were randomly assigned 1:1 to pembro 200 mg IV Q3W or placebo + CRT. PROs included the EORTC QLQ-C30 and EORTC QLQ-H&amp;N35. Responses to each item of the QLQ-C30 and H&amp;N35 were analyzed descriptively based on treatment group combined data. Each item was evaluated overall, and then for the H&amp;N35 by tumor location and by clinical event (death, distant progressive disease [PD], local regional PD, local PD, and distant metastasis or histologically persistent/residual disease). Symptom burden was defined as responses of “a little,” “quite a bit,” “very much,” or “yes.” Items associated with high symptom burden (≥30% of responses “quite a bit,” “very much,” or “yes”) at baseline were analyzed over time. Results: Of 756 pts with PRO data, highly endorsed items (≥50% experiencing the symptom) on the QLQ-C30 at baseline were pain, trouble sleeping, needing rest, tiredness, and worry; highly endorsed (≥50%) items from the H&amp;N35 were pain in mouth, painful throat, problems swallowing solid food, coughing, hoarseness, and use of pain killers. Pts with an event, compared to pts who were event-free at the time of data cut-off, experienced greater symptom burden at baseline; for example, pain in mouth (56% vs 50%), pain in jaw (47% vs 37%), use of pain killers (71% vs 58%), weight loss (53% vs 30%), trouble eating (63% vs 46%), and problems swallowing solid food (69% vs 56%). Symptoms at baseline also differed by primary tumor location, demonstrating the heterogeneity of symptom burden across this population. Based on the threshold of ≥30% reporting worse responses at baseline, 20 items on the H&amp;N35 were analyzed over time. Of pts who experienced an event (n = 345, 46%), 6 items met this threshold: pain in mouth (32%), problems swallowing solid food (41%), trouble eating (32%), use of pain killers (71%), use of nutritional supplements (34%), and weight loss (53%). For these items, a similar or greater percentage of pts with symptoms were observed over time in those who had events compared to those with no events. Conclusions: Observations of pts enrolled in KEYNOTE-412 study who had events, appearing to have greater symptom burden at baseline, suggests there may be a relationship between baseline item scores and clinical outcomes. Heterogeneity of populations may lead to variability of baseline PRO scores and should be considered in PRO analysis. Further research is needed to explore the relationship between baseline PROs and event outcomes as well as additional subgroup analysis. Clinical trial information: NCT03040999 .

Immunotherapy related patient-reported outcomes from five randomized controlled trials in patients with triple negative breast cancer: A systematic review.

e23167 Background: Immunotherapy (IO) has improved clinical outcomes in patients with early-stage Triple Negative Breast Cancer (TNBC) receiving neoadjuvant therapy and certain patient subsets in the metastatic setting. This study aims to evaluate IO-related Patient-Reported Outcomes (PRO) in patients older than 65 years. Methods: We searched Medline ALL (Ovid), Embase (Elsevier), Cochrane Central (Wiley), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. The searches combined terms reflecting (1) the immune checkpoint inhibitors atezolizumab, durvalumab, and pembrolizumab; (2) breast cancer; and (3) randomized controlled trials. Results were limited to items published in English from 2013 through September 2023. We excluded review articles and clinical trial records without results. Two independent reviewers (C.S. and M.L.) screened the studies using the systematic review management tool Covidence, and conflicts were resolved by a third reviewer (W.I.Z.). We included studies that reported on PRO in adults with TNBC receiving any of the three immunotherapies of interest. Results: Five publications composed of two peer-reviewed papers and three abstracts were identified, including 3878 total patients and 3184 with PRO. Three pembrolizumab studies had 2643 total patients (2056 with PRO) and two atezolizumab studies (IMPASSION 130, IMPASSION 031) had 1235 total patients (1128 with PRO). The PRO analysis in KEYNOTE 522 included 1145 patients in the neoadjuvant phase and 847 in the adjuvant phase. The PRO analysis in KEYNOTE 355 included total 847 patients and 317 with Combined Positive Score (CPS) ≥10. No study specified PRO data for patients older than 65 years. Baseline completion rates for all studies were &gt; 80%. All studies used standardized PRO instruments, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC- QLQ C30) and its Breast Cancer Module (QLQ-BR23), the Functional Assessment of Cancer-Therapy-General (FACT-G GP5), and the EuroQol-5 Dimension (EQ-D5). All studies showed no statistical difference, or clinical meaningful decline in PRO endpoints between patients who received chemo with IO versus chemo with placebo, during and post treatment follow up. The PRO analysis from KEYNOTE 119, which included total 594 patients of which 187 had CPS ≥10, demonstrated that patients receiving single agent chemotherapy had worse PROs related to systemic therapy side effects and hair loss while the pembrolizumab group had decreased worry about future health. None included subgroup analysis by age, including patients older than 65 years. Conclusions: Our systematic review demonstrates that in both early and advanced TNBC, IO did not worsen PRO. Prospective and retrospective data in IO-related PRO in older patient population are needed.

Icarifil® in Association with Daily Use of Tadalafil (5 mg) versus Standard Tadalafil Daily Dose (5 mg) or Alone: Results from a Controlled, Randomized Clinical Trial.

Background: The management of erectile dysfunction (ED) shows several grey zones and new treatments are required to reduce the percentage of patients discontinuing treatment. Here, we aim to evaluate the role of a natural mixture named Icarifil® (L-Citrulline, L-Carnitine, Eruca vesicaria, Panax ginseng, Tribulus terrestris, Turnera diffusa, Taurine, Vitamin E, Zinc) in the management of patients with ED. Methods: From September 2022 to March 2023, all patients attending 3 urological institutions due to ED were randomized to receive the following for 3 months: Icarifil® 1 sachet every 24 h (Group 1) or Icarifil® 1 sachet + tadalafil 5 mg 1 tablet every 24 h (Group 2) or tadalafil 5 mg 1 tablet daily (Group 3). All patients underwent urologic visits and dedicated questionnaires (IIEF-5, SEP-2, SEP-3) at enrollment and at the follow-up evaluation (3 months). Patient-Reported Outcomes (PROs) at the follow-up evaluation were used. The primary endpoint was the difference in the questionnaires at the follow-up visit compared to the one at enrollment among the study groups. Results: In the per-protocol analysis, 52 patients in Group 1, 55 in Group 2 and 57 in Group 3 were analyzed. At the follow-up evaluation, IIEF-5 scores improved in all the 3 groups between enrollment and the follow-up evaluation, but a statistically significant difference was reported between Group 2 (+7.4) and Group 1 (+4.1) or Group 3 (+5.1), (p < 0.001; p < 0.001). Moreover, 47 patients (94.0%) in Group 2 showed an improvement in the SEP questionnaires, when compared with the baseline, while 29 in Group 1 (56.9%) and 42 in Group 3 (82.3%) showed a statistically significant difference (p = 0.004; p = 0.003) among the groups. The PRO analysis reported better efficacy and patient satisfaction in Group 2 when compared with Group 1 or Group 3. Conclusions: In conclusion, Icarifil® is able to improve penile erectile function in mild-moderate ED and significantly improve the clinical efficacy of daily used tadalafil 5 mg. Icarifil® could represent an interesting alternative treatment in patients experiencing adverse effects or with contraindications for chronic treatment with PDE5-is.

Patient-reported outcomes (PROs) with talazoparib (TALA) plus enzalutamide (ENZA) vs. placebo (PBO) plus ENZA in men with metastatic castration-resistant prostate cancer (mCRPC): Subgroup analysis of patients with novel hormonal therapy (NHT) pretreatment in the TALAPRO-2 study.

116 Background: In TALAPRO-2 (NCT03395197), TALA +ENZA vs PBO + ENZA demonstrated significant improvement in radiographic progression-free survival, a manageable adverse event (AE) profile, and a delay in time to definitive clinical meaningful deterioration in global health status (GHS)/quality of life (QoL) overall and across all pre-specified subgroups. This post hoc analysis evaluated PROs in patients with prior NHT treatment. Methods: PROs were assessed on day 1 and scheduled visits (every 4 weeks until week 53 then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. PRO analyses, performed in NHT-pretreated/ patients for GHS/QoL functional and symptom scales, included on treatment comparison of overall change from baseline (per longitudinal repeated measures mixed-effects model). Results: Of the 805 men randomized and treated, 49 patients were included in this subgroup analysis (TALA + ENZA n= 22, PBO + ENZA n= 27). A statistically significant and clinically meaningful estimated overall change from baseline favored TALA + ENZA in physical functioning (20.5 [95% confidence interval {CI}: 8.8, 32.2]; P=0.0007), role functioning (20.4 [95% CI 4.8, 35.9]; P=0.0103), pain (32.9 [95% CI 50.3, 15.5]; P=0.0002), and constipation (12.5 [24.4, 0.6]; P=0.0399). No significant differences disfavoring TALA + ENZA were observed. Conclusions: In these subgroup analyses of NHT pretreated patients, significant differences in PROs favoring TALA + ENZA were observed. Results should be interpreted with caution given the small sample sizes and exploratory nature of this analysis. Clinical trial information: NCT03395197 .

EMBARK post hoc analysis of sexual activity (SA) patient-reported outcome (PRO) measures.

313 Background: In the phase 3 EMBARK trial (NCT02319837), enzalutamide (ENZ) + leuprolide (L) and ENZ monotherapy (mono) delayed metastasis-free survival (MFS) vs placebo (P) + L without impairing global health-related quality of life (HRQoL) in high-risk biochemically recurrent (BCR) nonmetastatic hormone-sensitive prostate cancer (nmHSPC) (PSA doubling time ≤9 months). A prespecified PRO analysis showed that SA (measured as a composite score using European Organization for Research and Treatment of Cancer QoL Questionnaire-Prostate 25 [QLQ-PR25]) was better preserved with ENZ mono vs P + L and no significant difference between ENZ + L vs P + L. A post hoc analysis at the HRQoL item level was conducted to understand the effect on SA in each comparison and enable shared decision-making between physicians and patients. Methods: Men with high-risk BCR nmHSPC were randomized (1:1:1) to ENZ + L (double blind), ENZ mono (open label), and P + L (double blind). HRQoL was assessed at baseline and every 12 weeks until metastasis/death. This post hoc analysis assessed effects on time to confirmed (two consecutive visits) deterioration (TTCD) using predefined thresholds of one category decline from baseline in sexual interest, activity, satisfaction, erectile function, and feeling like a man using QLQ-PR25 item 50; QLQ-PR25 item 51; FACT-P item GS7; FACT-P item BL5; and FACT-P item P5 measures, respectively (Table). Intent-to-treat principle was applied. Results: At baseline, 327–332 men per arm completed the PRO surveys; overall completion rates were ≥85%, except for GS7 (≤36% due to voluntary response). ENZ mono vs P + L : TTCD in items 50 (interest) and 51 (activity), GS7 (satisfaction), and BL5 (erectile function) was delayed with ENZ mono. ENZ + L vs P + L: no significant differences in TTCD were observed, except a shorter TTCD by a median 0.06 months in BL5 (erectile function) with ENZ + L (Table). Conclusions: This post hoc item-level analysis of the EMBARK trial confirmed that SA was better preserved with ENZ mono vs P + L in terms of interest, activity, satisfaction, and maintaining erection. Further, the SA PROs were similar between ENZ + L and P + L, implying there is no further SA burden when adding ENZ to androgen-deprivation therapy. Clinical trial information: NCT02319837 . [Table: see text]

Avelumab first-line maintenance (1LM) for advanced urothelial carcinoma (aUC): Long-term patient-reported outcomes (PROs) in the phase 3 JAVELIN Bladder 100 trial.

581 Background: In the JAVELIN Bladder 100 trial, avelumab 1LM + best supportive care (BSC) significantly prolonged overall survival vs BSC alone in patients (pts) with aUC that had not progressed with 1L platinum-based induction chemotherapy, and health-related quality of life was maintained. We report long-term and exploratory PRO analyses in the overall avelumab + BSC arm (any treatment duration) and in the subgroup with ≥12 months of avelumab treatment. Methods: In JAVELIN Bladder 100 (NCT02603432), PROs were a secondary endpoint assessed at baseline, on day 1 of each 4-week cycle, at end of treatment/withdrawal, and up to 90 days post treatment. PRO instruments used were National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol 5 Dimensions 5 Levels (EQ-5D-5L). Descriptive and mixed-effect model analyses were conducted. Data were not evaluated in the BSC alone arm because few pts remained on study treatment at later time points. Results: At data cutoff (Jun 4, 2021), median follow-up in the avelumab arm (n=350) was 38.0 months (≥2 years in all pts), and median duration of treatment was 5.8 months. In pts treated for ≥12 months (n=118 [33.7%]), baseline characteristics were similar to those in the overall avelumab + BSC arm, except for a higher proportion with ECOG performance status of 0 (70.3% vs 60.9%) and lower proportion with visceral metastases (47.5% vs 54.6%). In both populations, completion rates for both PRO instruments among evaluable pts were &gt;80% at all time points during treatment. On average, PRO scores remained stable throughout treatment, and no clinically relevant changes from baseline were reported (Table). Among pts treated for ≥12 months, ≈75% of evaluable pts reported no change or a decrease in being bothered by treatment side effects throughout 24 months of treatment. Conclusions: Prolonged avelumab 1LM treatment (≥12 months) was associated with stable PROs, indicating preservation in quality of life. The results further support the use of avelumab 1LM until progression or unacceptable toxicity as standard of care with level 1 evidence in pts with aUC who are progression-free after platinum-based chemotherapy. Clinical trial information: NCT02603432 . [Table: see text]

Treatment of Severely Shortened or Comminuted Clavicular Fractures in Older Adolescent Athletes

Background: Recent evidence suggests that for completely displaced midshaft clavicular fractures, surgery offers no clear benefit over nonoperative treatment in a general adolescent population from 10 to 18 years of age. However, the comparative outcomes of comminuted and/or severely shortened clavicular fractures specifically in older adolescent athletes have not been explored in a focused, methodologically rigorous fashion. Hypothesis: The study hypothesis was that outcomes would be superior in older adolescent athletes who underwent operative treatment compared with nonoperative treatment for comminuted and/or severely shortened clavicular fractures. Study Design: Cohort study; Level of evidence, 2. Methods: A level 2, multicenter, prospective cohort study investigating the outcomes of midshaft fractures in adolescents between 2013 and 2017 was filtered to analyze the subcohorts of athletes 14 to 18 years of age with either fracture comminution or fracture shortening of ≥25 mm or both. Patient characteristics, injury mechanisms, fracture characteristics, and treatments were compared. Complications, rates, timing of return to sports (RTS), and patient-reported outcomes (PROs) were analyzed. Results: The 2 treatment groups, which included 136 older adolescent athletes (69 nonoperative, 67 operative), showed similar distributions of primary sport type, competition level, comminution, shortening, and 2-year PRO response rate (n = 99; 73%). The operative group demonstrated 3 mm–greater mean superior displacement, which was therefore statistically controlled for as a confounder in the comparative PRO analysis. No 2-year differences in nonunion, delayed union, symptomatic malunion, refracture, clinically significant complications, or rates of RTS were detected between treatment groups. The difference in timing of RTS (operative, 10.3 weeks; nonoperative, 13.5 weeks) was statistically significant. After controlling for the minor difference in superior displacement, regression analysis and matched comparison cohorts demonstrated no differences between the nonoperative and operative groups in mean or dichotomized PRO scores. Conclusion: In this prospective, multicenter cohort study investigating older adolescent athletes with comminuted and/or severely shortened clavicular fractures, contrary to the study hypothesis, there were no differences in complications, RTS, or PROs between nonoperatively and operatively treated patients at 2 years. Comparably excellent outcomes of severe clavicular fractures in adolescent athletes can be achieved with nonoperative treatment.

Changes over time in patient-reported outcomes in patients with heart failure.

This paper describes the trajectory during 1year of four patient-reported outcomes (PROs), namely, sleep, depressive symptoms, health-related quality of life (HrQoL), and well-being, in patients with heart failure (HF), their relationshipand the patient characteristics associated with changes in these PROs. Data analyses of PROs from 603 patients (mean age 67years; 29% female, 60% NYHA II) enrolled in the HF-Wii study. On short term, between baseline and 3months, 16% of the patients experienced continuing poor sleep, 11% had sustained depressive symptoms, 13% had consistent poor HrQoL, and 13% consistent poor well-being. Across the entire 1-year period only 21% of the patients had good PRO scores at all timepoints (baseline, 3, 6, and 12months). All others had at least one low score in any of the PROs at some timepoint during the study. Over the 12months, 17% had consistently poor sleep, 17% had sustained symptoms of depression, 15% consistently rated a poor HrQoL, and 13% poor well-being. Different patient characteristics per PRO were associated with a poor outcomes across the 12months. Age, education, New York Heart Association, and length of disease were related to two PRO domains and submaximal exercise capacity (6min test), co-morbidity, and poor physical activity to one. In total, 79% of the patients with HF encountered problems related to sleep, depressive symptoms, HrQoL, and well-being at least once during a 1-year period. This underscores the need for continuous monitoring and follow-up of patients with HF and the need for dynamic adjustments in treatment and care regularly throughout the HF trajectory.

Quality of Life with Nivolumab and AVD First-Line Treatment in Hodgkin Lymphoma: Patient-Reported Outcomes from the Phase II GHSG Nivahl Trial

Background: First-line treatment of patients with classical Hodgkin lymphoma (HL) with anti-PD1 antibodies in combination with AVD chemotherapy is highly effective across risk-groups. Based on encouraging phase II and ongoing phase III trials, anti-PD1 based first-line treatment may hence soon become a first-line treatment option. To date, no patient-reported outcome (PRO) data is available in this setting, which is crucial to comprehensively evaluate relative benefits of these novel treatment approaches. Herein, we present the preplanned PRO analysis of quality of life (QoL), fatigue and life situation of HL patients treated within the randomized GHSG phase II NIVAHL trial. Methods: NIVAHL enrolled 109 patients aged 18-60 years with first diagnosis of early-stage unfavorable HL to receive either fully concomitant (4xN-AVD; group A) or sequential (4xN, 2xN-AVD, 2xAVD; group B) nivolumab-based 1st-line treatment, each followed by 30Gy involved-site radiotherapy (IS-RT). The primary and final analyses showed excellent efficacy and an acceptable safety profile after 1- and 3-years of follow up; details were previously published (Bröckelmann et al. JAMA Oncol 2020 &amp; JCO 2023). Patients providing separate informed consent reported QoL and Fatigue by the EORTC QLQC30 questionnaire in addition to key sociodemographic data including employment status at baseline and after systemic treatment, radiotherapy and 1- and 3-years of follow-up (FU), respectively. Data were analyzed descriptively and time-to-recovery (TTR) calculated for resolution of fatigue (TTR-F, event defined as first documentation of a fatigue score &amp;lt;30 after end-of-treatment (EOT)) and return to work (TTR-W, event defined as first documentation of employment after EOT). Results: A total of 99 patients provided a median of 4 questionnaires per patient (range 1-11), with the vast majority (85%) providing baseline and at least one questionnaire during FU. Mean fatigue score was 22 points higher (95% confidence interval, CI 16.1-27.9) than the age- and sex-matched German reference population at baseline, worsened during treatment (+38.2, 95%CI 31.4-44.9) but improved over the course of FU (1-year +10.2, 95%CI 3.7-16.6) to normal values at 3-year FU (-3.4, 95%CI -10.7 to 3.9), without any differences between treatment groups. Similar trajectories were observed for global health status/QoL as well as the different functional and symptom scales. While improvement beyond baseline (79.6, 95%CI 76.5-82.7) was observed, global health status/QoL did not improve to age- and sex-matched reference values at 1- (87.2, 95%CI 83.2-91.2) and 3-year FU (92, 95%CI 87.8-96.2). Multiple regression analysis showed a significant effect of baseline score (ß 0.28-0.56) and age (ß 0.23-0.34) but not sex (p&amp;gt;0.2 each) on cognitive, emotional and social functional scales as well as fatigue at 1-year of FU. At 3-years of FU the effect of age remained significant (ß 0.48-0.66) for all functional or symptom scales except resolution of dyspnea, while baseline scores had no significant effect. More detailed analysis of the different QLQ-C30 scales is ongoing and will be presented at the meeting. Median TTR-F and TTR-W were 12.8 (95%CI 7.3-20.3) and 3.8 months (95%CI 1.4-8.0) after EOT, respectively. Cox regression analysis for TTR-F showed significant effect of baseline fatigue (HR 0.99, p=0.03) but not sex (HR 1.71, p=0.09) or age (HR 0.98, p=0.14). For TTR-W, Cox regression did not show significant effects of baseline fatigue (HR 1, p=0.93) or age (HR 0.99, p=0.69) but a trend for faster return to work in male patients (HR 1.82, p=0.06). Conclusion: This first ever analysis of PROs after anti-PD1 based first-line HL treatment with N-AVD indicates substantial improvement of functional and symptom scales as well as global health status/QoL at last FU compared to baseline. Baseline status and age have a significant effect for improvement of functioning and symptoms at 1-year of FU. Importantly, while substantial fatigue is present at baseline, relevant improvement with resolution to age- and sex-matched reference values is observed and recovery is influenced by baseline fatigue score.

Longitudinal Patient-Reported Outcomes (PROs) in a Prospective Registry of CAR T-Cell Therapy Recipients

Background Chimeric antigen receptor T-cell therapies (CAR-T) significantly improve survival and health-related quality of life (HRQoL) in clinical trials of relapsed hematologic malignancies. However, the impact of CAR-T on real-world longitudinal patient-reported outcomes (PROs), particularly in the immediate post-CAR-T period during which patients are hospitalized and at risk for acute CAR-T-related toxicities, has not been studied. Further, few CAR-T studies have utilized Patient-Reported Outcomes Measurement Information System (PROMIS) survey instruments, which are recommended to enable comparison of PROs across various CAR-T products and disease types. To characterize real-world HRQoL and symptom burden in patients receiving CAR-T, we integrated PROMIS PRO instruments into a prospective cellular therapy registry. Methods The University of Chicago Cellular Therapy Biobank prospectively administers the PROMIS v1.2 Global Health and PROMIS-29 Profile v2.1 instruments to CAR-T recipients. PRO instruments are administered at the following timepoints, anchored to the day (D) of CAR-T receipt: baseline (at time of apheresis), D+1, D+15, D+28, D+90, D+180, and then every 3 months until the 2-year timepoint. The Biobank was queried for all patients who completed a baseline and at least one post-CAR-T survey. PROMIS T-scores were analyzed by one-way repeated measures ANOVA up to the 12-month timepoint. PROMIS T-scores were longitudinally visualized as mean change from baseline. Minimally important differences (MID) that were clinically significant were defined as T-score changes of at least 2. Statistical analyses were performed in STATA, version 17.0. Results There were 68 patients available for PRO analysis. Median age was 65 years (range, 24-80) and 63% were male. Most patients had large B-cell lymphomas (n = 27, 40%) or multiple myeloma (n = 27, 40%). Median prior lines of therapy were 4 (range, 1-12), with only 3 patients receiving 1 prior therapy. The majority of patients received CD19-targeted products (n = 35, 51%), followed by BCMA-targeted products (n = 27, 40%). Patients lived a median of 36 miles from the CAR-T center (range, 2-544), with 65% living over 30 miles away. Survey completion rates at timepoints were as follows: 73% at D+15, 82% at D+28, 84% at D+90, 76% at D+180, and 95% at 12 months. For PROMIS Global Health, there was a significant longitudinal change in Global Physical Health (p = .002), with a clinically meaningful improvement by D+28 which was no longer observed by D+90 ( Figure 1), but no significant change in Global Mental Health (p = .09). For PROMIS-29 Profile, there were significant longitudinal changes in physical function (p = .0001), fatigue (p = .001), and social role functioning (p = .002), but not anxiety (p = .08), depression (p = .45), sleep (p = .92), or pain (p = .27). There were clinically meaningful improvements in both physical and social role functioning in the first 28 days after CAR-T which were no longer observed by D+90 ( Figure 1). Fatigue significantly worsened in the first 28 days after CAR-T to a clinically meaningful degree, but subsequently improved to better than baseline after D+90 ( Figure 2). With a median follow-up of 9 months (range, 1-28), 40% of patients had post-CAR-T disease progression. Relapses occurred a median of 4.9 months after CAR-T, with 31% of relapses (n = 8) occurring before D+90. There were 10 deaths (15%) at a median of 6.7 months after CAR-T. Conclusions In this real-world prospective PRO analysis, there were clinically meaningful improvements in several HRQoL domains in the first month after CAR-T, namely physical and social functioning, despite significantly worsening fatigue during the same time period. However, these HRQoL improvements diminished after D+28, concurrent with the transition of patients from the CAR-T center to home. These results suggest that intensive support by the inpatient and outpatient care teams may improve physical HRQoL during the immediate post-CAR-T period. In addition, given the low rate of relapses before D+90 in this cohort, worsening patient-reported functioning after D+28 may be driven by changes in care support after discharge to home. Interventions to optimize the post-CAR-T transition to home are warranted, as well as studies utilizing PROMIS PROs to identify patients with deteriorating HRQoL who may benefit from augmented support and/or closer surveillance for relapsed disease.

Patient-Reported Outcomes in Acute Myeloid Leukemia Patients with FLT3-ITD Mutation Receiving Quizartinib Vs. Standard Chemotherapy: Results from the Quantum-First Trial

Introduction: QuANTUM-First (NCT02668653) is a multicenter, global, randomized, double-blind phase 3 clinical trial evaluating the efficacy and safety of the novel oral fms-like tyrosine kinase 3 inhibitor (FLT3i) quizartinib in combination with standard induction and consolidation chemotherapy, and as maintenance monotherapy for up to 36 cycles in patients 18-75 years old with FLT3-ITD positive acute myeloid leukemia (AML). Quizartinib demonstrated a clinically meaningful and statistically significant improvement in overall survival (OS) versus placebo. An exploratory endpoint of the trial was to assess the impact of quizartinib on patient-reported outcomes (PROs). This is the first report of the longitudinal results of the PRO measures (PROMs) collected in the QuANTUM-First trial. Methods: Patients were randomized to receive chemotherapy + quizartinib or chemotherapy + placebo. PROMs were the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) and EuroQol EQ-5D-5L. Baseline measurement was collected on day 8 of the first induction cycle, and repeated measurements were collected on day 28 of induction cycles 1-2, day 6 and 28 of consolidation cycles 1-4, and day 1 of continuation cycles 1-34 at 3-cycle intervals. EORTC QLQ-C30 and EQ-5D-5L scores were calculated as per their respective scoring manuals and included mean (95% CI, p-value) score for each domain of the EORTC QLQ-C30 and EQ-5D-5L index score, as well as mean change from baseline score at each timepoint. A minimal clinically important difference (MCID) score ≥10 points for each domain of the EORTC QLQ-C30, was considered clinically meaningful. A mixed-effect model for repeated measures (MMRM) and time until definitive deterioration (TUDD) was used to assess the longitudinal impact of treatment on PROs. TUDD was defined as time from baseline PRO score to first deterioration of the score beyond the MCID as compared to the baseline without further improvement of more than one MCID as compared to the reference score or without any further available score. Results: A total of 509 out of 539 patients from the trial (254 quizartinib; 255 placebo) were included for PRO analysis. Patient compliance to questionnaire completion at the beginning of each phase was high and similar for both arms and most scales (Global Health Status [GHS] completion rate (%) on induction cycle 1, consolidation cycle 1, and continuation cycle 1: 99.2, 95.3, 93.4, respectively) Baseline PRO scores were comparable between arms and were lower than the general population norm EORTC QLQ-C30 and EQ-5D-5L scores for EU and US (Table 1). Per MMRM, there were clinically meaningful improvements from baseline in GHS (Figure 1) and fatigue in both arms. However, there was no significant difference between arms for the change from baseline score although placebo arm had numerically better scores specifically during the maintenance phase (treatment difference for quizartinib - placebo was -2.0 [95% CI: -4.8, 0.7], p=0.1479 for GHS and 3.0 [95% CI: -0.1, 6.1], p=0.0600 for fatigue). Similar trends towards clinically meaningful improvement in score over time for both arms and no significant differences between arms were observed in most of the functional and symptom scales of EORTC QLQ-C30 and EQ-5D-5L index scores. By TUDD analysis, quizartinib arm showed slower deterioration in several scales (specifically GHS, cognitive function, appetite loss, and constipation) but the differences did not reach statistical significance. Conclusions: QuANTUM-First is the first study to explore the impact of quizartinib on PROs. Quizartinib showed improvement in OS without any detrimental impact on quality of life and symptoms when added to standard chemotherapy followed by maintenance monotherapy in patients with newly diagnosed FLT3-ITD AML.

Statistical methods and data visualisation of patient-reported outcomes in early phase dose-finding oncology trials: a methodological review

Traditionally, within dose-finding clinical trials, treatment toxicity and tolerability are assessed by clinicians. Research has shown that clinician reporting may have inadequate inter-rater reliability, poor correlation with patient reported outcomes, and under capture the true toxicity burden. The introduction of patient-reported outcomes (PROs), where the patient can assess their own symptomatic adverse events or quality of life, has potential to complement current practice to aid dose optimisation. There are no international recommendations offering guidance for the inclusion of PROs in dose-finding trial design and analysis. Our review aimed to identify and describe current statistical methods and data visualisation techniques employed to analyse and visualise PRO data in published early phase dose-finding oncology trials (DFOTs). DFOTs published from June 2016-December 2022, which presented PRO analysis methods, were included in this methodological review. We extracted 35 eligible papers indexed in PubMed. Study characteristics extracted included: PRO objectives, PRO measures, statistical analysis and visualisation techniques, and whether the PRO was involved in interim and final dose selection decisions. Most papers (30, 85.7%) did not include clear PRO objectives. 20 (57.1%) papers used inferential statistical techniques to analyse PROs, including survival analysis and mixed-effect models. One trial used PROs to classify a clinicians' assessed dose-limiting toxicities (DLTs). Three (8.6%) trials used PROs to confirm the tolerability of the recommended dose. 25 trial reports visually presented PRO data within a figure or table within their publication, of which 12 papers presented PRO score longitudinally. This review highlighted that the statistical methods and reporting of PRO analysis in DFOTs are often poorly described and inconsistent. Many trials had PRO objectives which were not clearly described, making it challenging to evaluate the appropriateness of the statistical techniques used. Drawing conclusions based on DFOTs which are not powered for PROs may be misleading. With no guidance and standardisation of analysis methods for PROs in early phase DFOTs, it is challenging to compare study findings across trials. Therefore, there is a crucial need to establish international guidance to enhance statistical methods and graphical presentation for PRO analysis in the dose-finding setting. EA has been supported to undertake this work as part of a PhD studentship from the Institute of Cancer Research within the MRC/NIHR Trials Methodology Research Partnership. AM is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust, the Institute of Cancer Research and Imperial College.

Patient-Reported Outcomes of Omission of Breast Surgery Following Neoadjuvant Systemic Therapy

Patients should have an active role in decisions about pursuing or forgoing specific therapies in treatment de-escalation trials. To evaluate longitudinal patient-reported outcomes (PROs) encompassing decisional comfort and health-related quality of life (HRQOL) among patients who elected to enroll in a clinical trial evaluating radiotherapy alone, without breast surgery, for invasive breast cancers with exceptional response to neoadjuvant systemic therapy (NST). Prospective, single-group, phase 2 clinical trial at 7 US medical centers. Women aged 40 years or older with invasive cT1-2 N0-1 M0 triple-negative or human epidermal growth factor receptor 2 (ERBB2)-positive breast cancer with no pathologic evidence of residual disease following standard NST enrolled from March 6, 2017, to November 9, 2021. Validated PRO measures were administered at baseline and 6, 12, and 36 months post-radiotherapy. Data were analyzed from January to February 2023. PRO measures included the Decision Regret Scale (DRS), Functional Assessment of Cancer Therapy-Lymphedema (FACT-B+4), and Breast Cancer Treatment Outcomes Scale (BCTOS). Changes in PRO measure scores and subscores over time. Among 31 patients, the median (IQR) age was 61 (56-66) years, 26 (84%) were White, and 26 (84%) were non-Hispanic. A total of 15 (48%) had triple-negative disease and 16 (52%) had ERBB2-positive disease. Decisional comfort was high at baseline (median [IQR] DRS score 10 [0-25] on a 0-100 scale, with higher scores indicating higher decisional regret) and significantly increased over time (median [IQR] DRS score at 36 months, 0 [0-20]; P < .001). HRQOL was relatively high at baseline (median [IQR] FACT-B composite score 121 [111-134] on a 0-148 scale, with higher scores indicating higher HRQOL) and significantly increased over time (median [IQR] FACT-B score at 36 months, 128 [116-137]; P = .04). Perceived differences between the affected breast and contralateral breast were minimal at baseline (median [IQR] BCTOS score 1.05 [1.00-1.23] on a 1-4 scale, with higher scores indicating greater differences) and increased significantly over time (median [IQR] BCTOS score at 36 months, 1.36 [1.18-1.64]; P < .001). At 36 months postradiotherapy, the cosmetic subscore was 0.45 points higher than baseline (95% CI, 0.16-0.74; P = .001), whereas function, pain, and edema subscores were not significantly different than baseline. In this nonrandomized phase 2 clinical trial, analysis of PROs demonstrated an overall positive experience for trial participants, with longitudinal improvements in decisional comfort and overall HRQOL over time and minimal lasting adverse effects of therapy. ClinicalTrials.gov Identifier: NCT02945579.

Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer

ObjectiveTo determine the impact on overall survival (OS) and patient-reported outcomes (PROs) of combining atezolizumab with standard therapy for newly diagnosed stage III/IV ovarian cancer. MethodsThe placebo-controlled double-blind randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial (NCT03038100) assigned eligible patients to 3-weekly atezolizumab 1200 mg or placebo for 22 cycles with platinum-based chemotherapy and bevacizumab. Coprimary endpoints were progression-free survival (already reported) and OS in the PD-L1-positive and intent-to-treat (ITT) populations, tested hierarchically. Prespecified PRO analyses focused on disease-related abdominal pain and bloating symptoms (European Organisation for Research and Treatment of Cancer QLQ-OV28), functioning, and health-related quality of life (HRQoL) (QLQ-C30). ResultsAfter 38 months’ median follow-up, the OS hazard ratio in the PD-L1-positive population was 0.83 (95% CI, 0.66–1.06; p = 0.13); median OS was not estimable with atezolizumab versus 49.2 months with placebo. The hazard ratio for OS in the ITT population was 0.92 (95% CI, 0.78–1.09; median 50.5 versus 46.6 months, respectively). At week 9, similar proportions of patients in both arms of the neoadjuvant cohort showed ≥10-point improvement from baseline in abdominal pain and bloating, functioning, and HRQoL. In the primary surgery cohort, similar proportions of patients in each arm had improved, stable, or worsened physical and role function and HRQoL from baseline over time. Neither cohort showed differences between arms in treatment-related symptoms or overall side-effect bother. ConclusionsIncorporation of atezolizumab into standard therapy for newly diagnosed ovarian cancer does not significantly improve efficacy or impose additional treatment burden for patients.ClinicalTrials.gov registration: NCT03038100.

Cancer therapy-associated thrombosis: A patient- reported outcomes (PROs) analysis.

e18819 Background: Cancer patients have a higher rate of thrombotic events (TEs) compared to the general population. Site, stage and treatment related factors, among others, contribute to this increased risk. Regarding treatment, various anticancer agents have been linked with increased risk of TEs. However, despite the incidence and impact of TEs, available data is inadequate, and most PRO-based analyses focus on individual agents. This analysis aims to utilise PROs to identify correlations between several anticancer agents and the incidence of TEs. Methods: CareAcross is an online interactive platform which collects Patient Reported Outcomes and provides support to cancer patients based on their condition and needs. Specific cancer treatments are among the collected data. Additionally, breast and lung cancer patients engaging with the platform were asked to report, among others, whether they have had a TE during their cancer journey. Data was aggregated and anonymised in order to evaluate the likelihood of TEs for each cancer treatment. Results: Based on data captured as of February 2023, 2011 breast (13% metastatic) and 573 lung (51% metastatic) cancer patients from 8 (mostly European) countries had provided real world data on cancer treatments and TEs. Among them, 144 (7.2%) breast cancer and 97 (16.9%) lung cancer patients reported TEs. Breast cancer treatments with higher than average association with TEs included aromatase inhibitors (8.1% of 569), tamoxifen (8.0% of 462), trastuzumab (9.0% of 221), CDK4/6 inhibitors (8.7% of 126). Among lung cancer treatments, cisplatin was associated with higher incidence than carboplatin (20.0% of 110 vs 13.4% of 112); others included pembrolizumab (21.8% of 78), pemetrexed (13.2% of 68), alectinib (29.4% of 34), osimertinib (12.1% of 33), afatinib (29% of 31). The Table provides a summary for this subset of anticancer agents. Conclusions: Based on the analysis of PROs from the CareAcross platform, it is confirmed that lung cancer patients have a higher risk of TEs compared to breast cancer patients. Moreover, certain anticancer agents appear to be linked with increased risk of TEs. In breast cancer, aromatase inhibitors and tamoxifen show similar association; in lung cancer, cisplatin appears to be a stronger factor compared to carboplatin. Finally, it is worth mentioning that some immunotherapies and targeted agents in lung cancer were found to have strong association with TEs. More PROs would improve the accuracy of these findings. [Table: see text]

Patient-reported outcomes (PROs) among men receiving talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase 3 study (TALAPRO-2).

5013 Background: TALAPRO-2 (NCT03395197) showed statistically significant improvement in radiographic progression free survival with TALA + ENZA (n=402) vs PBO + ENZA (n=403) (HR=0.63 95% CI 0.51-0.78; P&lt;0.001) in men receiving 1L treatment for mCRPC. Here we report PRO endpoints from TALAPRO-2. Methods: PROs were assessed at day 1 (baseline) and at scheduled visits until radiographic progression (every 4 weeks until week 53, and then every 8 weeks) using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. Prespecified PRO analyses included overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to definitive clinically meaningful (≥10-point change) deterioration (TTD). Between-arm comparisons of TTD were made using a stratified log-rank test and a Cox proportional hazards model. Results: Of the 805 men randomized and treated, 793 had a baseline score followed by at least 1 post-baseline score; TALA + ENZA (n=395), PBO + ENZA (n=398). Although the treatment effect on global health status (GHS)/quality of life (QoL) significantly favored PBO + ENZA, the predefined threshold of clinical meaningfulness was not met; moreover, no significant differences between the arms were observed in any functioning scales. A significantly longer TTD in GHS/QoL was observed for TALA + ENZA; HR=0.780 (95% CI: 0.62, 0.99), P=0.038; median: 30.8 months vs 25.0 months. A numerical greater delay in TTD in urinary symptoms was longer for TALA + ENZA; HR=0.759 (95% CI: 0.543, 1.061), P=0.105; median not reached vs 35.9 months. Additional PRO results will be presented. Conclusions: Compared with PBO + ENZA, in the TALA + ENZA arm there was 1) a modest deterioration disfavoring GHS/QoL (deterioration was not clinically meaningful based on the predefined threshold), and 2) a maintenance in all functioning scales. TTD in GHS/QoL was significantly longer with TALA + ENZA vs PBO + ENZA, reflecting improved disease control. These results complement the benefit-risk assessment of TALAPRO-2. Clinical trial information: NCT03395197 . [Table: see text]