A core outcome domain set to assess cutaneous neurofibromas related to neurofibromatosis type 1 in clinical trials
Authors: Fertitta Laura , Bergqvist Christina , Sarin Kavita Y , Plotkin Scott R , Moertel Christopher , Petersen Andrea K , Cannon Ashley , Berman Yemima , Pichard Dominique C , Röhl Class , Lessing Andres , Brizion Bernadette , Peiffer Bastien , Ravaud Philippe , Tran Viet-Thi , Armand Marie-Laure , Moryousef Sabine , Ferkal Salah , Jannic Arnaud , Ezzedine Khaled , Wolkenstein Pierre ,   the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) international collaboration, Adsit Sarah , Ahlawat Shivani , Alcantara Krizelle , Anderson Rosemary , Anstett Kara , Aouad Lisa , Avery Rob , Barnett-Tapia Carolina , Barton Belinda , Batlle Catherine , Bedwell David , O'Brian Tammy Benson , Berg Dale , Bergqvist Christina , Berman Yemima , Bettegowda Chetan , Blakeley Jaishri , Brainin Rob , Dirksen Sara Brebbia , Buono Frank , Buono Susan , Cai Wenli , Campen Cynthia , Cannon Ashley , Carpenter Kelly , Cellucci Alexandra , Champollion Nicolas , Chang Long-Shen , de Blank Peter , del Castillo Allison , Didier Laura , Dombi Eva , Erickson Gregg , Evans Gareth , Ezzedine Khaled , Faber Onno , Fertitta Laura , Fisher Michael , Franklin Barbara , Garrett Edith , Gibson-Williams Madalyn , Giovannini Marco , Glad Dani , Gold Deborah , Goodkind Adam , Goto Kayo , Grabowski Jane , Grasso Vito , Gross Andrea , Grotti Lorenza , Gutmann David , Haberkamp Diana , Haebich Kristine , Hahn Cindy , Hanemann Oliver , Hingtgen Cynthia , Hocking Matt , Hunt Eric , Hussey Maureen , Janke Kelly , Janusz Jennifer , Jordan Justin , Kaer Valerie , Karajannis Matthias , Keeling Kim , Kesterson Bob , Kim Aerang , Kim Hannah , Kim Yoori , Klein-Tasman Bonnie , Klesse Laura , Koetsier Kimberley , Komlodi-Pasztor Edina , Larson Noelle , Leier Andre , Leif Erica , Lessing Andres , Listernick Robert , Loftspring Elana , Loftspring Sharon , Ina Ly K , Manth Linda , Martin Staci , McKnight Sherri , McManus Miranda , Merker Vanessa , Morehouse Elizabeth , Moss Irene , Mukabenov Lara , Newman Patricia , Oberlander Beverly , Payne Jonathan , Peterson Drea , Pichard Dominque , Pierpoint Rene , Plotkin Scott , Pope Dorothy , Popplewell Linda , Pride Natalie , Ratley Marcus , Rhodes Steven , Rios Jonathan , Ristow Inka , Riter Bill , Rohl Claas , Romo Carlos , Rosenberg Adam , Rosser Tena , Samblanet Jessica , Sarin Kavita , Sarnoff Herb , Schneider Natalie , Schorry Elizabeth , Sell Mary , Sheard Steven , Silverman Dani , Simpson Brittany , Smith Melissa , Sorman Connie , Staedtke Verena , Stavinoha Pete , Stemmer-Rachamimov Anat , Stevenson David , Sundby Taylor , Thompson Heather , Ullrich Nicole , Upadhyaya Meena , van de Vrie Marjan , Viskochil Dave , Vitte Jeremie , Walker James , Wallace Jo , Wallis Deann , Walsh Karin , Weaver Shannon , Weisman Hannah , Welling Bradley , Widemann Brigitte , Wirtanen Tracy , Wolkenstein Pierre , Wolters Pamela , Achtziger Wong Mary , Zhou Jiangbing 
Published: October 2023

Abstract

Background
Cutaneous neurofibromas (cNF) are considered one of the highest burdens of neurofibromatosis type 1 (NF1). To date, no medical treatment can cure cNF or prevent their development. In that context, there is an urgent need to prepare and standardize the methodology of future trials targeting cNF.

Objectives
The objective was to develop a core outcome domain set suitable for all clinical trials targeting NF1-associated cNF.

Methods
The validated approach of this work consisted of a three-phase methodology: (i) generating the domains [systematic literature review (SLR) and qualitative studies]; (ii) agreeing (three-round international e-Delphi consensus process and working groups); and (iii) voting.

Results
(i) The SLR and the qualitative studies (three types of focus groups and a French e-survey with 234 participants) resulted in a preliminary list of 31 candidate items and their corresponding definitions. (ii) A total of 229 individuals from 29 countries participated in the first round of the e-Delphi process: 71 patients, relatives or representatives (31.0%), 130 healthcare professionals (HCPs, 56.8%) and 28 researchers, representatives of a drug regulatory authority, industry or pharmaceutical company representatives or journal editors (12.2%). The overall participation rate was 74%. After round 2, five candidate items were excluded. Between rounds 2 and 3, international workshops were held to better understand the disagreements among stakeholders. This phase led to the identification of 19 items as outcome subdomains. (iii) The items were fused to create four outcome domains (‘clinical assessment’, ‘daily life impact’, ‘patient satisfaction’ and ‘perception of health’) and prioritized. The seven items that did not reach consensus were marked for the research agenda. The final core outcome domain set reached 100% of the votes of the steering committee members.

Conclusions
Although numerous outcomes can be explored in studies related to cNF in NF1, the present study offers four outcome domains that should be reported in all trial studies, agreed on by international patients, relatives and representatives of patients; HCPs; researchers, representatives of drug regulatory authorities or pharmaceutical companies and journal editors. The next step will include the development of a set of core outcome measurement instruments to further standardize how these outcomes should be assessed.