Prior elicitation of the efficacy and tolerability of Methotrexate and Mycophenolate Mofetil in Juvenile Localised Scleroderma

Yasin Desai; Thomas Jaki; Michael W Beresford; Thomas Burnett; Despina Eleftheriou; Heidi Jacobe; Valentina Leone; Suzanne Li; Pavel Mozgunov; Athimalaipet V Ramanan; Kathryn S Torok; Marina E Anderson; Jordi Anton; Tadej Avcin; Jessie Felton; Ivan Foeldvari; Bisola Laguda; Flora McErlane; Lindsay Shaw; Francesco Zulian; Clare E Pain

doi:10.12688/amrcopenres.13008.1

Prior elicitation of the efficacy and tolerability of Methotrexate and Mycophenolate Mofetil in Juvenile Localised Scleroderma

AMRC Open Res. 2021 Sep 9:3:20. doi: 10.12688/amrcopenres.13008.1. eCollection 2021.

Authors

Yasin Desai¹, Thomas Jaki^{1

2}, Michael W Beresford^{3

4}, Thomas Burnett¹, Despina Eleftheriou^{5

6}, Heidi Jacobe⁷, Valentina Leone⁸, Suzanne Li⁹, Pavel Mozgunov¹, Athimalaipet V Ramanan¹⁰, Kathryn S Torok¹¹, Marina E Anderson^{12

13}, Jordi Anton¹⁴, Tadej Avcin¹⁵, Jessie Felton¹⁶, Ivan Foeldvari¹⁷, Bisola Laguda¹⁸, Flora McErlane¹⁹, Lindsay Shaw^{6

10}, Francesco Zulian²⁰, Clare E Pain³

Affiliations

¹ MPS Research Unit, Department of Mathematics and Statistics, Lancaster University, Lancaster, LA1 4YF, UK.
² MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK.
³ Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, L12 2AP, UK.
⁴ Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L69 3BX, UK.
⁵ University College London Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
⁶ Department of Paediatric Rheumatology, Great Ormond St Hospital NHS Foundation Trust, London, WC1N 3JH, UK.
⁷ UT Southwestern Medical Center, Dallas, Texas, TX 75390, USA.
⁸ Paediatric Rheumatology Department, Leeds Children Hospital (Leeds Teaching Hospitals) and University of Leeds, Leeds, LS1 3EX, UK.
⁹ Department of Pediatrics, Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center & Hackensack Meridian School of Medicine, Hackensack, New Jersey, NJ 07601, USA.
¹⁰ University Hospitals Bristol NHS Foundation Trust & Translational Health Sciences, Bristol, BS1 3NU, UK.
¹¹ Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15260, USA.
¹² Department of Rheumatology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, L9 7AL, UK.
¹³ Lancaster Medical School, Lancaster University, Lancaster, LA1 4YF, UK.
¹⁴ Pediatric Rheumatology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Barcelona, 08007, UK.
¹⁵ Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Centre, Ljubljana, 1000 Ljubljana, Slovenia.
¹⁶ Department of Dermatology, Brighton and Sussex University Hospitals & Royal Alexandra Children's Hospital, Brighton, BN2 1DH, UK.
¹⁷ Hamburg Centre for Pediatric and Adolescence Rheumatology, Hamburg, 22081 Hamburg, Germany.
¹⁸ Department of Paediatric Dermatology, Chelsea and Westminster Hospital, London, SW10 9NH, UK.
¹⁹ Department of Paediatric Rheumatology, Great North Children's Hospital, Newcastle, NE1 4LP, UK.
²⁰ Department of Woman's and Child's Health, University of Padova, Padua, 35122 Padua, Italy.

Abstract

Background: Evidence is lacking for safe and effective treatments for juvenile localised scleroderma (JLS). Methotrexate (MTX) is commonly used first line and mycophenolate mofetil (MMF) second line, despite a limited evidence base. A head to head trial of these two medications would provide data on relative efficacy and tolerability. However, a frequentist approach is difficult to deliver in JLS, because of the numbers needed to sufficiently power a trial. A Bayesian approach could be considered.

Methods: An international consensus meeting was convened including an elicitation exercise where opinion was sought on the relative efficacy and tolerability of MTX compared to MMF to produce prior distributions for a future Bayesian trial. Secondary aims were to achieve consensus agreement on critical aspects of a future trial.

Results: An international group of 12 clinical experts participated. Opinion suggested superior efficacy and tolerability of MMF compared to MTX; where most likely value of efficacy of MMF was 0.70 (95% confidence interval (CI) 0.34-0.90) and of MTX was 0.68 (95% CI 0.41-0.8). The most likely value of tolerability of MMF was 0.77 (95% CI 0.3-0.94) and of MTX was 0.62 (95% CI 0.32-0.84). The wider CI for MMF highlights that experts were less sure about relative efficacy and tolerability of MMF compared to MTX. Despite using a Bayesian approach, power calculations still produced a total sample size of 240 participants, reflecting the uncertainty amongst experts about the performance of MMF.

Conclusions: Key factors have been defined regarding the design of a future Bayesian approach clinical trial including elicitation of prior opinion of the efficacy and tolerability of MTX and MMF in JLS. Combining further efficacy data on MTX and MMF with prior opinion could potentially reduce the pre-trial uncertainty so that, when combined with smaller trial sample sizes a compelling evidence base is available.

Keywords: Bayesian approach; juvenile localised scleroderma; methotrexate; mycophenolate mofetil; prior elicitation.

Associated data

figshare/10.6084/m9.figshare.14994486.v1

Grants and funding

The author(s) declared that no grants were involved in supporting this work.