Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria.

Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.

Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition.

Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.

Patient Experience Survey of Anti-Vascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema.

INTRODUCTION: Understanding patient perspectives of treatment may improve adherence and outcomes. This study explored real-world patient experiences with anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD). METHODS: This multinational, non-interventional, quantitative, cross-sectional, observational survey assessed treatment barriers/burden, patient-reported visual functioning, and treatment satisfaction in DME and nAMD patients in the USA, the UK, Canada, France, Italy, and Spain. Treatment patterns and visual outcomes were extracted from medical charts. Regression models evaluated relationships between adherence, total missed visits, number of anti-VEGF injections, and clinical and patient-reported outcomes for visual functioning. Association between treatment satisfaction and aspects of burden were assessed. RESULTS: The survey was completed by 183 DME and 391 nAMD patients. Patients had moderately high vision-related functioning (25-item National Eye Institute Visual Functioning Questionnaire score: mean = 74.8) and were satisfied with their current treatment (mean total score: Macular Disease Treatment Satisfaction Questionnaire = 59.2; Retinopathy Treatment Satisfaction Questionnaire = 61.3). Treatment satisfaction scores were worse with higher time-related impacts of treatment (nAMD/DME), higher impacts on finances and daily life (nAMD), negative impacts on employment and lower expectations for treatment effectiveness (DME). Most patients reported ≥1 barrier (66.1% DME, 49.2% nAMD patients) related to treatment (35.0%), clinic (32.6%), and COVID-19 (21.1%). Moreover, 44.9% of patients reported some impairment in activities of daily living. Work absenteeism was observed among >60% of working patients. Nearly one-quarter (24.2%) of patients needed ≥1 day to recover from intravitreal injections; most reported ≥30 min of travel time (73.7%) and clinic wait time (54.2%). In unadjusted univariable analyses, treatment adherence (vs. nonadherence) was related to higher most recent visual acuity (ß = 8.98 letters; CI, 1.34-16.62) and lower odds of visual acuity below driving vision (≤69 letters) (OR = 0.50; CI, 0.25-1.00). CONCLUSION: More durable treatments with reduced frequency of injections/visits may reduce treatment burden and improve patient satisfaction, which may enhance adherence and visual outcomes.

Caregiver Experience Survey of Anti-Vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema and Neovascular Age-Related Macular Degeneration.

INTRODUCTION: Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) require frequent anti-vascular endothelial growth factor (VEGF) treatment and monitoring visits. We aimed to understand the burden of treatment on caregivers. METHODS: This multinational, noninterventional study used a cross-sectional survey of adult patients with DME or nAMD treated with anti-VEGF injections in the USA, Canada, France, Italy, Spain, and the UK. The survey assessed caregivers' sociodemographic characteristics, patient relationships, patients' clinical history and treatment experiences, caregivers' experiences, and the Caregiver Reaction Assessment of caregiving burden. RESULTS: Caregivers for patients with DME (n = 30) and nAMD (n = 95) completed surveys. Mean ± standard deviation (SD) age was 64.0 ± 13.4 years, and most were female (71.2%), white (70.4%), married (66.4%), and from Europe (67.2%). Most were caring for their mother/father or partner/spouse (85.6%). Mean ± SD length of time as a caregiver was 9.1 ± 10.0 years. Caregivers estimated they provided support for 4.2 ± 2.9 days/week and 6.0 ± 7.1 h/day on average. Nearly half of caregivers (45.6%) reported some impairment in daily activities, and more than two-thirds (70.5%) of working caregivers (n = 44) reported work absenteeism due to anti-VEGF treatment/monitoring appointments. At least one treatment barrier was reported by 66.7% and 50.5% of caregivers of patients with DME and nAMD, respectively, which were related to coronavirus disease 2019- (38.4%), clinic- (18.4%), social-/health- (13.6%), treatment- (10.4%), or financial-related factors (4.8%). Caregiver Reaction Assessment scores indicated mild-to-moderate burden, with higher caregiver schedule disruption scores associated with an increasing number of anti-VEGF treatment/monitoring visits among DME caregivers (r = 0.61). CONCLUSION: Caregivers devote substantial time to caregiving, leading to schedule disruptions and absenteeism for some working caregivers. Positive and negative impacts on caregiver mental health were reported.

The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria.

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade-naive (part 2) and C5 inhibitor-treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor-pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).

Health-related quality of life with fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Results from the randomized, phase 3 CLL14 trial.

Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least eight points at cycle three, whereas improvement was delayed until cycle eight with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients.

Evaluation of the Measurement Properties of Four Performance Outcome Measures in Patients with Elective Hip Replacements, Elective Knee Replacements, or Hip Fractures.

OBJECTIVES: To evaluate the measurement properties of four performance outcome (PerfO) measures (timed up and go, four-step stair climb, long stair climb, and repeated chair stand) in three patient populations(elective total hip replacement [eTHR], elective total knee replacement [eTKR], and hip fracture [HF]). METHODS: A cross-sectional and longitudinal design was used to assess the PerfO measurement properties using the US Food and Drug Administration guidance for industry around patient-reported outcome measures to support labeling claims. Patient-reported outcome measures and patient- and clinician-reported global concept items were completed along with four PerfO measures at visit 1 and two follow-up visits. Measurement properties assessed included reliability, construct validity, ability to detect change, and estimates of meaningful change. RESULTS: A total of 280 patients (100 eTHR, 105 eTKR, and 75 HF) were recruited, with most (n = 276) providing data at visit 1. Most of the patients were female (64%) and retired (64%), and had at least one comorbidity (91%). Inter-rater and test-retest reliability ranged from good to excellent (0.73 ≤ intraclass correlation coefficient ≤ 0.95) for each PerfO measure. Known-groups validity was demonstrated for all PerfO measures, with those reporting less pain better physical functioning and those who did not use an assistive device having quicker mean completion times. Construct validity and ability to detect change were demonstrated and estimates of meaningful change derived. CONCLUSIONS: This study found the measurement properties of four PerfO measures in samples of patients with eTHR, eTKR, and HF to be supported for consideration of future use, and provided estimates for interpretation of change.

A Comparison of the Nomological Networks Associated With Forced-Choice and Likert Formats of the Narcissistic Personality Inventory.

The Narcissistic Personality Inventory (NPI) is one of the most popular measures of narcissism. However, its use of a forced-choice response set might negatively affect some of its psychometric properties. The purpose of this research was to compare a Likert version of the NPI, in which only the narcissistic response of each pair was given, to the original NPI, in 3 samples of participants (N = 1,109). To this end, we compared the nomological networks of the forced-choice and Likert formats of the NPI in relation to alternative measures of narcissism, narcissistic personality disorder, entitlement, self-esteem, general personality traits (reported by self and informants), interpersonal styles, and general pathological traits included in the DSM-5. The Likert format NPI-total and subscales-manifested similar construct validity to the original forced-choice format across all criteria with only minor differences that seem to be due mainly to the increased reliability and variability found in the Likert NPI Entitlement/Exploitativeness subscale. These results provide evidence that a version of the NPI that employs a Likert format can justifiably be used in place of the original.

Gender Role Discrepancy Stress, High-Risk Sexual Behavior, and Sexually Transmitted Disease.

Nearly 20 million new sexually transmitted infections occur every year in the United States. Traditionally, men have demonstrated much greater risk for contraction of and mortality from STDs perhaps because they tend to engage in a number of risky sexual activities. Research on masculinity suggests that gender roles influence males' sexual health by encouraging risk-taking behavior, discouraging access to health services, and narrowly defining their roles as partners. However, despite the propensity of highly masculine men to engage in high-risk sexual behavior, there is reason to suspect that men at the other end of the continuum may still be driven to engage in similar high-risk behaviors as a consequence of gender socialization. Discrepancy stress is a form of gender role stress that occurs when men fail to live up to the ideal manhood derived from societal prescriptions (i.e., Gender Role Discrepancy). In the present study, we surveyed a national sample of 600 men via Amazon Mechanical Turk to assess perceived gender role discrepancy, experience of discrepancy stress, and the associations with risky sexual behavior and potential contraction of STDs. Results indicated that men who believe they are less masculine than the typical man (i.e., gender role discrepancy) and experience distress stemming from this discrepancy (i.e., discrepancy stress) engage in high-risk sexual behavior and are subsequently diagnosed with more STDs. Findings are discussed in relation to implications for primary prevention strategies.

Masculine discrepancy stress, substance use, assault and injury in a survey of US men.

To understand and ultimately prevent injury and behavioural health outcomes associated with masculinity, we assessed the influence of masculine discrepancy stress (stress that occurs when men perceive themselves as falling short of the traditional gender norms) on the propensity to engage in stereotypically masculine behaviours (eg, substance use, risk taking and violence) as a means of demonstrating masculinity. Six-hundred men from the USA were recruited via Amazon's Mechanical Turk (MTurk) online data collection site to complete surveys assessing self-perceptions of gender role discrepancy and consequent discrepancy stress, substance use/abuse, driving while intoxicated (DWI) and violent assaults. Negative binomial regression analyses indicated significant interactive effects wherein men high on gender role discrepancy and attendant discrepancy stress reported significantly more assaults with a weapon (B=1.01; SE=0.63; IRR=2.74; p=0.05) and assaults causing injury (B=1.01; SE=0.51; IRR=2.74; p<0.05). There was no association of discrepancy stress to substance abuse, but there was a protective effect of gender role discrepancy for DWI among men low on discrepancy stress (B=-1.19, SE=0.48; IRR=0.30; p=0.01). These findings suggest that gender role discrepancy and associated discrepancy stress, in particular, represent important injury risk factors and that prevention of discrepancy stress may prevent acts of violence with the greatest consequences and costs to the victim, offender and society.