Health-related quality of life of children with neurofibromatosis type 1:Analysis of proxy-rated PedsQL and CHQ questionnaires

This study aims to (1) investigate health-related quality of life (HRQoL) in children with Neurofibromatosis Type 1 (NF1) using the Pediatric Quality of Life inventory (PedsQL) and the Child Health Questionnaire (CHQ); and (2) compare the psychometric properties and content of these questionnaires in NF1 patients. PedsQL and CHQ proxy-reports were administered to parents/caregivers of 160 patients with NF1 aged 5–12 years. HRQoL scores were compared with Dutch population norms using independent t-tests. Psychometric properties (feasibility and reliability) were assessed by floor/ceiling effects and Cronbach's alpha coefficient. A principal component analysis (PCA) with varimax rotation was performed to identify the data's internal structure. By content mapping, we identified unique constructs of each questionnaire. Proxy-reported HRQoL was significantly lower on all PedsQL subscales for children aged 5–7 years, and on 4/6 subscales for children aged 8–12 years compared to norms. Significantly lower HRQoL was reported on 6/14 CHQ subscales (children 5–7 years) and 9/14 subscales (children 8–12 years). The PedsQL showed slightly better feasibility and reliability. The PCA identified two components, representing psychosocial and physical aspects of HRQoL, explaining 63% of total variance. Both questionnaires showed relevant loadings on both components. The CHQ subscales concerning parents and family were considered unique contributions. Proxy-reported HRQoL of children with NF1 is significantly lower compared to norms on multiple domains. Both questionnaires adequately measure HRQoL in children with NF1. However, the PedsQL has slightly better psychometric properties, while the CHQ covers a unique dimension of HRQoL associated with disease impact on parents and family.</p

Quality of life in individuals with neurofibromatosis type 1 associated cutaneous neurofibromas:validation of the Dutch cNF-Skindex

Background: Almost all patients with Neurofibromatosis type 1 (NF1) develop cutaneous neurofibroma (cNF), benign dermal tumours that have a large impact on the patient’s Quality of Life (QoL). The French cNF-Skindex is the first questionnaire to specifically assess cNF-related QoL in patients with NF1. We aimed to adapt and validate a Dutch version of the cNF-Skindex. Methods: The questionnaire was translated using forward and backwards translation, and subsequently administered to a sample of 59 patients on two separate occasions. Feasibility was evaluated by the presence of floor/ceiling effects. Reliability was assessed by evaluating internal consistency and test-retest reliability, by calculating Cronbach’s alpha and Spearman’s rank correlation coefficients. The EQ-5D-5L and SF-36 were used to evaluate convergent validity, using Spearman’s rank correlation coefficients. An exploratory factor analysis was performed to study the data’s internal structure. Multivariable linear regression was used to model the relationship between patient characteristics and the cNF-Skindex. Results: The Dutch cNF-Skindex demonstrated excellent feasibility and reliability (Cronbach’s alpha 0.96, test-retest correlation coefficient 0.88). Convergent validity was confirmed for the EQ-5D-5L and relevant SF-36 scales. All items and subdomains from the original questionnaire were confirmed following exploratory factor analysis. The patient characteristics included in the multivariable linear regression were not significantly associated with the cNF-Skindex score. Conclusions: The Dutch cNF-Skindex displayed excellent psychometric properties, enabling use in the Netherlands.</p

Quality of life in individuals with neurofibromatosis type 1 associated cutaneous neurofibromas:validation of the Dutch cNF-Skindex

Background: Almost all patients with Neurofibromatosis type 1 (NF1) develop cutaneous neurofibroma (cNF), benign dermal tumours that have a large impact on the patient’s Quality of Life (QoL). The French cNF-Skindex is the first questionnaire to specifically assess cNF-related QoL in patients with NF1. We aimed to adapt and validate a Dutch version of the cNF-Skindex. Methods: The questionnaire was translated using forward and backwards translation, and subsequently administered to a sample of 59 patients on two separate occasions. Feasibility was evaluated by the presence of floor/ceiling effects. Reliability was assessed by evaluating internal consistency and test-retest reliability, by calculating Cronbach’s alpha and Spearman’s rank correlation coefficients. The EQ-5D-5L and SF-36 were used to evaluate convergent validity, using Spearman’s rank correlation coefficients. An exploratory factor analysis was performed to study the data’s internal structure. Multivariable linear regression was used to model the relationship between patient characteristics and the cNF-Skindex. Results: The Dutch cNF-Skindex demonstrated excellent feasibility and reliability (Cronbach’s alpha 0.96, test-retest correlation coefficient 0.88). Convergent validity was confirmed for the EQ-5D-5L and relevant SF-36 scales. All items and subdomains from the original questionnaire were confirmed following exploratory factor analysis. The patient characteristics included in the multivariable linear regression were not significantly associated with the cNF-Skindex score. Conclusions: The Dutch cNF-Skindex displayed excellent psychometric properties, enabling use in the Netherlands.</p

Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis:A potential model for rare diseases

Background Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.Methods Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts.Results The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF.Conclusions These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials

Optimizing expert and patient input in pediatric trial design : lessons learned and recommendations from a collaboration between conect4children and European Patient‐CEntric ClinicAl TRial PLatforms

Advice from multiple stakeholders is required to design the optimal pediatric clinical trial. We present recommendations for acquiring advice from trial experts and patients/caregivers, derived from advice meetings that were performed through a collaboration of the Collaborative Network for European Clinical Trials for Children (c4c) and the European Patient‐CEntric ClinicAl TRial PLatforms (EU‐PEARL). Three advice meetings were performed: (1) an advice meeting for clinical and methodology experts, (2) an advice meeting for patients/caregivers, and (3) a combined meeting with both experts and patients/caregivers. Trial experts were recruited from c4c database. Patients/caregivers were recruited through a patient organization. Participants were asked to provide input on a trial protocol, including endpoints, outcomes, and the assessment schedule. Ten experts, 10 patients, and 13 caregivers participated. The advice meetings resulted in modification of eligibility criteria and outcome measures. We have provided recommendations for the most effective meeting type per protocol topic. Topics with limited options for patient input were most efficiently discussed in expert advice meetings. Other topics benefit from patient/caregiver input, either through a combined meeting with experts or a patients/caregivers‐only advice meeting. Some topics, such as endpoints and outcome measures, are suitable for all meeting types. Combined sessions profit from synergy between experts and patients/caregivers, balancing input on protocol scientific feasibility and acceptability. Both experts and patients/caregivers provided critical input on the presented protocol. The combined meeting was the most effective methodology for most protocol topics. The presented methodology can be used effectively to acquire expert and patient feedback

The PlexiQoL, a patient-reported outcome measure on quality of life in neurofibromatosis type 1-associated plexiform neurofibroma:translation, cultural adaptation and validation into the Dutch language for the Netherlands

Background: Half of the patients with Neurofibromatosis type 1 (NF1) develop one or more tumours called plexiform neurofibromas, which can have a significant impact on Quality of Life (QoL). The PlexiQoL questionnaire is a disease-specific QoL measure for adults with NF1-associated plexiform neurofibromas. The aim of this study was to adapt and validate a Dutch version of the PlexiQoL for the Netherlands. Methods: The PlexiQoL was translated using the dual-panel methodology, followed by cognitive debriefing interviews to assess face and content validity. The psychometric properties were evaluated by administering the questionnaire on two separate occasions to a sample of adults with NF1 and plexiform neurofibromas. Feasibility was evaluated by the presence of floor/ceiling effects. Reliability was assessed by evaluating Cronbach’s alpha coefficient and test-retest reliability, using Spearman’s rank correlation coefficients. Mann-Whitney U tests were used to check for known group validity. The Nottingham Health Profile (NHP) questionnaire was used as comparator questionnaire to evaluate convergent validity. Results: The translation and cognitive debriefing interviews resulted in a Dutch version of the PlexiQoL that reflected the original concept and underlying semantic meanings of the UK English version. Forty participants completed the validation survey. The Dutch PlexiQoL demonstrated excellent internal consistency (Cronbach’s α 0.825) and test-retest reliability (Spearman correlation coefficient 0.928). The questionnaire detected differences in PlexiQoL scores between participants based on self-reported general health and disease severity. Convergent validity was confirmed for relevant NHP subsections. Conclusions: The Dutch PlexiQoL demonstrated excellent psychometric properties and can be reliably used to measure plexiform neurofibroma-related QoL in adults with NF1 in the Netherlands.</p

Identifying challenges in Neurofibromatosis: a modified Delphi procedure

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are rare conditions with pronounced variability of clinical expression. We aimed to reach consensus on the most important manifestations meriting the development of drug trials. The five-staged modified Delphi procedure consisted of two questionnaires and a consensus meeting for 40 NF experts, a survey for 63 patient representatives, and a final workshop. In the questionnaires, manifestations were scored on multiple items on a 4-point Likert scale. The highest average scores for NF experts deciding the 'need for new treatment' were for malignant peripheral nerve sheath tumour (MPNST) (4,0) and high grade glioma (HGG) (3,9) for NF1; meningioma (3,9) for NF2 and pain (3,9) for SWN. The patient representatives assigned high scores to all manifestations, with plexiform neurofibroma being highest in NF1 (4,0), vestibular schwannoma in NF2 (4,0), and pain in SWN (3,9). Twelve experts participated in the consensus meeting and prioritised manifestations. MPNST was ranked the highest for NF1, followed by benign peripheral nerve sheath tumours. Tumour manifestations received highest ranking in NF2, and pain was the most prominent problem for SWN. Patient representative ratings for NF1 were similar to the experts' opinions, except that they ranked HGG as the most important manifestation. For NF2 and SWN, the patient representatives agreed with the experts. We conclude that NF experts and patient representatives consent to prioritise development of drug trials for MPNST, benign peripheral nerve sheath tumours, cutaneous manifestations and HGG for NF1; tumours for NF2; and pain for SWN

Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA