Letter to the Editor Patient-reported outcomes in NAFLD/NASH clinical trials: A blind spot that needs addressing To the Editor: collecting PRO data was the SF-36, which was planned to be used We read with interest the article by Younossi et al.,1 which in 8 trials. The NASH-CHECK was reported in 2 (0.6%) protocols. explored patient-reported outcomes (PROs) in non-alcoholic No significant differences were observed in the inclusion of steatohepatitis (NASH) populations. Although the authors PROs according to trial phase (phase II = 13, 4.5% vs. phase III = 4, comprehensively assessed the current knowledge and evidence 8.5%; p = 0.2) and funding source (industry-funded = 11, 5.3% vs. about the impact of NASH on PROs and highlighted the academic = 6, 4.6%; p = 0.7). Trial protocols including children importance of developing and implementing NASH-specific were more likely to include PROs than those that did not include PRO instruments in research endeavors in clinical practice, children (5/29, 17.2% vs. 12/305, 3.9%; p = 0.001). little is known about the inclusion of PROs in non-alcoholic The fact that only 5% of the NAFLD/NASH protocols regis- fatty liver disease (NAFLD)/NASH clinical trial protocols. Trial tered on clinicaltrials.gov reported the systematic collection of protocols serve as the foundation for planning and imple- PROs is worrying and reveals an overall lack of patient-centric menting clinical trials; thus, providing a glimpse of future trial appraisals in the quest for treatments against the most com- results. Therefore, including PRO measures in trial protocols mon chronic liver disease and one of the most prevalent chronic can provide essential data to inform shared decision-making conditions worldwide. The trend shown in Fig. 1B is discour- and improve clinical guidelines and health policy recommen- aging as it suggests that the number of clinical trials including dations. Furthermore, it could aid in addressing and mending PROs has barely increased in recent years. This is a matter of what the authors call “a significant and often unrecognized concern because NAFLD and NASH have a remarkable impact on health-related quality of life (HRQoL) burden among in- patients’ quality of life. Even if this is not being studied sys- dividuals with NASH”. tematically in clinical trials, there is evidence that some PROs To complement the authors’ work and learn about PROs in are related to the degree of fibrosis of NASH and therefore are NAFLD/NASH clinical trial protocols, we aimed to assess the valuable tools to gather information about patients’ HRQoL.2 proportion of NAFLD/NASH interventional trial protocols Moreover, their derivatives (focused on patients’ experiences) reporting the inclusion of PROs as predefined outcomes of in- are self-reporting instruments that measure the patients’ terest among protocol trials registered on clinicaltrials.gov. We perception while receiving care or participating in clinical reviewed the clinicaltrials.gov registry to explore whether PROs trials.3 are routinely included in NAFLD/NASH clinical trial protocols. The NASH-CHECK is the only specific PRO measure in the Using the keyword “non-alcoholic fatty liver disease,” we NAFLD/NASH field. This PRO measure was recently created and queried clinicaltrials.gov for NAFLD/NASH protocol trials. The validated in patients without cirrhosis.4 Some aspects included search was restricted to interventional, phase II-III trials. Rele- in the NASH-CHECK relate to symptoms such as pain, fatigue, vant protocol trial data was extracted and descriptively sum- itch, cognition, and sleep impact. These traits may impact daily marized to chart the available protocols registered on activities, social interactions, and the mental well-being of clinicaltrials.gov. patients with NASH. Overall, these symptoms and their effects By July 29, 2022, 334 interventional phase II and III NAFLD/ can impact work productivity, ability to work, cost of medica- NASH protocols were registered on clinicaltrials.gov. Of these, tion, and cost of lifestyle management, thus having a negative 284 (85%), 28 (8.4%), 12 (3.6%), and 6 (1.8%) investigated phar- economic impact. In the trials reported in this letter, only 2 out macological compounds, dietary supplements, biological com- of 334 studies reported using NASH-CHECK. Although the latter ponents, and behavioral interventions, respectively. In addition, finding is not surprising because the NASH-CHECK is a rela- two studies researched devices, and one investigated a blood tively young PRO measure, we expect future clinical trials to donation procedure. As shown in Fig. 1A, most protocols (86%) routinely include it as a pre-specified outcome measure in their were phase II trials, and roughly half were reported as trial protocols. Due to the increasing number of clinical trials completed. Less than 10% included children, and eight (2.4%) specifically for patients with cirrhosis, it is necessary to eluci- trials were designed to include only males. The industry was the date if a derivative of NASH-CHECK or another NASH-specific predominant source of funding for the protocols registered PRO measure for the population with cirrhosis should be (61.3%). Remarkably, only 5% of all registered protocols reported developed. PROs as outcomes of interest. The most common instrument for We urge NAFLD/NASH stakeholders to include patient per- spectives in clinical research to gain information beyond NAFLD- focused metrics and to improve our understanding of what matters to patients while participating in clinical trials. This will Keywords: Non-alcoholic fatty liver disease; Patient-reported outcomes; Health- help improve published trials’ quality and provide clinician- related quality of life; Non-alcoholic steatohepatitis. Received 19 August 2022; received in revised form 7 September 2022; accepted 13 scientists with data to further implement patient-centered care September 2022; available online 22 September 2022 for NAFLD. Letter to the Editor A Protocols in clinicaltrials.gov (n = 334) Trial phase Phase 2, n (%) 287 (86) Phase 3, n (%) 47 (14) Status Completed, n (%) 169 (50.6) Recruiting, n (%) 59 (17.6) Active not recruiting, n (%) 19 (5.7) Suspended/terminated/withdrawn, n (%) 53 (15.8) Unknown, n (%) 17 (5.1%) Age groups included in RCTs Included children, n (%) 29 (8.6) Included individuals >60 yr, n (%) 201 (60.1) Included only males, n (%) 8 (2.4) Funding source Industry, n (%) 205 (61.3) Academic, n (%) 129 (38.7) Reported PROs as an outcome of interest, n (%) 17 (5) SF-36, n (%) 8 (2.4) Health-related quality of life (not specified), n (%) 5 (1.5) NASH-check, n (%) 2 (0.6) PEDQOL, n (%) 2 (0.6) PROMIS fatigue questionnaire score, n (%) 2 (0.6) PGI-S, n (%) 1 (0.3) Food frequency questionnaire (FFQ), n (%) 1 (0.3) B 50 N of CTs per year 45 N of CTs reporting PROMs per year 40 35 30 25 20 15 10 5 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 Fig. 1. Characteristics of the NASH clinical trial protocols and representation of PROs. (A) Overview of trial protocol characteristics and PROs, (B) Number of NASH trial protocols and those including PROs per year (2001-2022). CT, clinical trials; NASH, non-alcoholic steatohepatitis; PROs, patient-reported outcomes. Financial support Authors’ contributions No funding was obtained to conduct the present work. Conceived and designed the analysis: JMP, RMN, EdS; Collected the data: EdS, RMN, JRE; Contributed data or analysis tools: RMN, EdS; Performed Conflict of interest the analysis: EdS, RMN; Wrote the paper: all authors; Supervision of the JMP reports receiving consulting fees from Boehringer Ingelheim and work: JMP; All authors provided significant intellectual contributions to Novo Nordisk. He has received speaking fees from Gilead and Intercept, as the final draft of the paper and approved it for journal submission. well as travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Data availability statement He also received funds from the European Commission/EFPIA IMI2 The data used to perform this research letter can be shared upon 853966-2, IMI2 777377, H2020 847989, and PI19/01898. All other au- reasonable request. thors: no conflicts. None of the authors have any personal conflict con- cerning the present manuscript. Supplementary data Please refer to the accompanying ICMJE disclosure forms for further Supplementary data to this article can be found online at https://doi.org/1 details. 0.1016/j.jhepr.2022.100597. JHEP Reports 2023 vol. 5 j 100597 2 References Author names in bold designate shared co-first authorship Elena Sena1 Ramiro Manzano-Nunez1 [1] Younossi Z, Aggarwal P, Shrestha I, Fernandes J, Johansen P, Augusto M, Jesus Rivera-Esteban1,2,3 et al. The burden of non-alcoholic steatohepatitis: a systematic review of Juan M. Pericas1,2,3,4,* health-related quality of life and patient-reported outcomes. JHEP Rep 2022;4(9):100525. [2] Heath L, Aveyard P, Tomlinson JW, Cobbold JF, Koutoukidis DA. Association 1 of changes in histologic severity of nonalcoholic steatohepatitis and Liver Unit, Vall d’Hebron Institute for Research, Barcelona, Spain; 2 changes in patient-reported quality of life. Hepatol Commun 2022 Jul:1–11. Liver Unit, Vall d’Hebron University Hospital, Barcelona, Spain; 3 [3] Ng CH, Lim WH, Chin YH, Yong JN, Zeng RW, Chan KE, et al. Living in the Universitat Autònoma de Barcelona, Bellaterra, Spain; non-alcoholic fatty liver disease silent epidemic: a qualitative systematic 4 Centros de Investigación Biomédica en Red, Enfermedades Hepáticas y review of patients’ perspectives. Aliment Pharmacol Ther 2022 Digestivas (CIBERehd), Madrid, Spain Aug;56(4):570–579. [4] Doward LC, Balp MM, Twiss J, Slota C, Cryer D, Brass CA, et al. Development of a patient-reported outcome measure for non-alcoholic steatohepatitis (NASH-CHECK): results of a qualitative study. Patient 2021;14(5):533–543. * Corresponding author. Address: Liver Unit, Vall d’Hebron University Hospital, Vall d’Hebron Institute for Research, Pg de la Vall d’Hebron 119-129, 08035, Barcelona, Spain. E-mail address: juanmanuel.pericas@vallhebron.cat (J.M. Pericas). JHEP Reports 2023 vol. 5 j 100597 3