Vertex Pharmaceuticals

Multi-component endpoints can be necessary in regulatory trials when diseases manifest heterogeneously across and within patients, as in many rare neurodevelopmental disorders, but they require explicit justification to support an evidence-based validity rationale consistent with the Food and Drug Administration's Patient-Focused Drug Development guidance for clinical outcome assessments (COAs). This paper presents a practical framework for constructing and evaluating that rationale. The framework emphasizes: selecting meaningful aspects of health (MAHs) that are important to patients and plausibly affected within the trial timeframe; defining component concepts of interest (COIs) and selecting fit-for-purpose COAs for each component; documenting component-level justification for interpreting COA scores as reflecting their COIs in the context of use; and providing endpoint-level justification for interpreting treatment effects on the aggregate value as reflecting effects on the MAH(s). It highlights key design choices, including component selection and prioritization with patient/caregiver input, transparent scoring and weighting strategies, handling missing data, and ensuring adequate precision for the proposed design and analysis plan, and describes risks unique to multi-component endpoints, including benefit dilution, harm masking, and interpretive ambiguity. When the trade-offs among different endpoint strategies are considered thoughtfully and explicitly communicated along with an endpoint rationale grounded in patient-focused evidence, multi-component endpoints can provide a credible, fit-for-purpose approach to evaluating treatment benefit in heterogeneous populations.

Highly effective CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) have improved outcomes in cystic fibrosis (CF), with many children now experiencing minimal respiratory symptoms. This raises questions about the need for continued hypertonic saline inhalation and airway clearance techniques (ACTs). In this prospective multicentre observational study, children with CF aged 6-17 years treated with ETI for ≥9 months reduced the prescribed frequency of hypertonic saline inhalation and ACTs from twice daily to once daily over 12 months. The primary outcome was change in lung clearance index (LCI). Secondary outcomes included spirometry, airway microbiology, antibiotic use, and respiratory symptoms. Analyses of longitudinal outcomes were performed using mixed-effects models RESULTS: Forty-six children were included from two Swedish CF centres. Mean (SD) LCI and FEV1% predicted at baseline were 6.6 (1.1) and 97.2 (6.1), respectively. During the 12 months following treatment reduction, LCI showed a small, non-significant improvement of -0.32 units (95% CI -0.67 to 0.03; P = 0.075), while FEV1% predicted remained stable (mean change 0.02%-points, 95% CI -2.74 to 2.77; P = 0.99). Respiratory symptoms were stable (mean change -2.9 points, 95% CI -9.8 to 4.1; P = 0.41). Antibiotic use decreased from 47 to 29 days per person-year, corresponding to a 39% reduction (95% CI 25%-50%; P < 0.001), with no clinically relevant changes in airway microbiology. Reduction to once-daily hypertonic saline inhalation and ACTs in children with CF treated with ETI was not associated with clinical deterioration over 12 months and was accompanied by reduced antibiotic use.

Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks-metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk-that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.

The goal of the Primary Sclerosing Cholangitis Symptom Assessment Project (PSC-SAP) is to develop reliable and valid PSC symptom measures for use in clinical trials. This article describes the process for customizing PROMIS® Fatigue and PROMIS® Cognitive Function short forms for adults with PSC. Relevant items from the PROMIS item banks were selected by matching findings from concept elicitation interviews. Participants were purposively selected for cognitive interviews if they were symptomatic with PSC-related fatigue or cognitive impairment and met general eligibility for PSC clinical trials. Interviews were recorded, transcribed, and coded. The precision of these PROMIS short forms for PSC to capture fatigue and cognitive function at different levels was analyzed. Participants' (n = 22) open-ended descriptions of fatigue and cognitive impairment were consistent with prior concept elicitation interviews. From the 95-item PROMIS Fatigue item bank, 13 items were selected that directly aligned with fatigue concepts described during concept elicitation. Data from the cognitive interviews confirmed that both measures possessed strong content validity, with items perceived as clear, relevant, and comprehensive. The PROMIS Fatigue Short Form-PSC exceeded the 0.90 reliability threshold for T-scores between 36 and 79; the PROMIS Cognitive Function Short Form-PSC exceeded the 0.90 threshold between T-scores of approximately 22 and 60. This study demonstrated the strength of PROMIS item banks to design PROMIS Fatigue and Cognitive Function short forms for adults with PSC. Once the psychometric properties of the PROMIS short forms are confirmed, these measures may be used to evaluate symptoms in PSC research and clinical trials.

Elexacaftor/tezacaftor/ivacaftor (ETI) has led to marked improvements in physical health outcomes but inconsistent findings regarding changes in mental and behavioral health outcomes for youth with cystic fibrosis (YWCF) and their caregivers. To describe the prevalence of mental/behavioral health symptoms in YWCF taking ETI and their caregivers, and to examine the association between caregiver and youth mental/behavioral health symptoms. In this cross-sectional study, 118 YWCF (ages 7-17) and their caregivers from 11 U.S. CF centers participated. Standardized self-report and parent-proxy screening measures assessed symptoms of depression, anxiety, attention deficit hyperactivity disorder (ADHD), externalizing behaviors, and sleep disturbance. Descriptive statistics summarized prevalence and Spearman Rho correlations were used to analyze associations. The point prevalence of mild or moderate/severe depressive symptoms was 23.3% (95% CI: 16, 31) for caregivers, 27.1% (95% CI: 15, 40) for children (ages 7-12), and 28.6% (95% CI: 18, 39) for adolescents (ages 13-17). The point prevalence for mild or moderate/severe anxiety symptoms was 23.1% (95% CI: 15, 31) for caregivers, 31.3% (95% CI: 18, 44) for children, and 18.8% (95% CI: 10, 28) for adolescents. Some YWCF exceeded clinical cutoffs for sleep disturbance (29.8-35.0%), attention (11.4-14.9%), and externalizing behavior (5.7-8.5%). Caregiver mental health scores and child mental/behavioral health scores were positively correlated (ρ = 0.20 - 0.52, p's < 0.05). Though most YWCF and caregivers report few to no mental/behavioral health symptoms, many still report clinically elevated levels, suggesting the continued need to screen for mental health concerns in the evolving context of highly effective CF treatment. Our results also indicate that screening should expand to areas beyond anxiety and depression, such as sleep, as well as the possible need for developing family-based mental health care.