Idiopathic Multicentric Castleman Disease (iMCD) is a rare cytokine-driven disorder associated with systemic inflammation, organ dysfunction, and a high symptom burden. The disease has an estimated prevalence of between 6.9 and 9.7 people per million. The symptom burden of iMCD is associated with multifarious impacts on daily life for people living with the condition, in areas including work/education, social life, travel, mobility, personal relationships, and sexual functioning. Despite this significant impact, no validated condition-specific measure exists to assess symptom burden in iMCD. This represents an important unmet need, as the primary approach to iMCD treatment is both symptom control and prevention of serious complications. A novel, condition-specific symptom burden scale for iMCD is therefore timely and important and would have significant value as a clinical tool, both in routine care and during clinical trials, for accurately assessing disease burden at diagnosis, during progression, and for treatment efficacy. The purpose of this mixed methods project is to develop a novel, valid and reliable symptom burden patient reported outcome measure (PROM) for iMCD. The project is international in scope (including U.S., U.K., Canada, Australia, New Zealand and Brazil) and involves close collaboration between multiple stakeholders, including patients, clinicians, industry representatives, and researchers. The work will proceed through four stages.

In Stage 1, draft PROM content will be generated from existing literature and expert opinions.

In Stage 2, the content validity of the draft PROM will be assessed in online qualitative interviews with people living with iMCD, with any revisions to the content decided in consultation with patient and expert advisors.

In Stage 3, the revised PROM will be administered alongside existing measures of symptom burden and/or health-related quality of life to evaluate its
psychometric performance and inform decisions on content for the final PROM. The PROM will be finalised based on the qualitative and quantitative
evidence generated in consultation with project advisors.

Finally, in Stage 4, the PROM will be re-administered to observe change in symptom burden over time. This will be complemented with qualitative interviews in a mixed methods design to estimate a minimally important clinical difference (MCID) for the measure. Throughout, the development of the measure follows U.S. Food and Drug Administration (FDA) regulatory guidance, with modifications for rare diseases as required.

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Objective:

The ISBUS study aims to develop a novel symptom burden scale for iMCD. The scale will provide a common metric for assessing progression and treatment outcomes.

The ISBUS scale will be used to assist in determining the start of treatment and longitudinally to assess patient wellbeing. It is intended that the scale be used in clinical practice or clinical trials.

Significance:

IMCD is a highly symptomatic disease, and the primary focus of clinical management remains symptom control and prevention of serious complications. Currently, there are no disease-specific assessments to measure symptom burden within this patient population. Ability to objectively assess the iMCD symptom burden using a PROM based on the occurrence, pattern and multiplicity of symptoms and associated impact on daily living will enable us to monitor the clinical trajectory in real-time. iMCD symptom burden PROM will allow to capture the impact of the fluctuating nature of iMCD symptoms and facilitate timely initiation of treatment, better symptom monitoring, better adherence, early detection of flare ups, and shared care leading to greater patient satisfaction and improved physician-patient communication.

The central aim of this project is to produce a valid and robust patient reported outcome measure (PROM) that can be used to assess symptom burden in people living with idiopathic Multicentric Castleman Disease (iMCD).

  1. Based on existing data, expert opinion, and lived experience, which items (and associated patient reported outcome measure (PROM) content) should be generated to accurately assess symptom burden in idiopathic Multicentric Castleman Disease (iMCD)?
  2. What refinements are necessary to PROM content to ensure: (a) sufficient content validity to capture symptom burden in iMCD; and (b) sufficient psychometric performance?
  3. Based on all available evidence, which final items (and associated PROM content) should be selected to optimally assess symptom burden in iMCD?
  4. What is the smallest difference (change) in scores on the new PROM considered to be clinically meaningful to people living with iMCD?

Co-Principal Investigators

Dr Anju Keetharuth
Senior Research Fellow
University of Sheffield
SCHARR

d.keetharuth@sheffield.ac.uk

Dr Philip Powell
Senior Research Fellow
University of Sheffield
SCHARR

p.a.powell@sheffield.ac.uk

Kelly Makarounas-Kirchmann
Principal
KMC Health Care

kelly@kmchealthcare.com

Dr Sudipto Mukherjee
Director of Rare Cancers and Blood
Diseases
Assistant Professor, Lerner College of
Medicine at CWRU
Cleveland Clinic
Cleveland, Ohio, United States

Co-Investigators

Professor Jill Carlton
Professor of Health Outcomes Research
University of Sheffield
SCHARR

Dr Clara Mukuria
Senior Research Fellow
University of Sheffield
SCHARR

Dr Antonio Adolfo Guerra Soares Brandão
Haematologist
Hospital Beneficencia Portuguesa

Dr Karthik Ramasamy
Associate Professor of Hematology &
Consultant Hematologist
University Of Oxford & Oxford University
Hospitals NHS Trust
Oxford, United Kingdom

Mr Francis Shupo
Global Director, Market Access and HEOR
Recordati Rare Diseases, United Kingdom

Strategic Collaborators

Ms Kelley Dacus
Senior Director, Medical Affairs
Recordati Rare Diseases, United States

Yildiz Kelahmetoglu
Associate Director Global Medical Affairs
Recordati Rare Diseases, United Kingdom

Castleman Disease Collaborative Network
(CDCN), United States

Professor Miles Prince
Epworth Private Hospital, Melbourne, VIC,
Australia

Dr Annmarie Bosco
Prince of Wales Hospital, Sydney, NSW,
Australia

Dr Satyen Gohil
University College London Hospitals NHS
Foundation Trust, London, United Kingdom

ISBUS Advisory Board

Dr Antonio Adolfo Guerra Soares Brandão
Hematologist, Hospital Beneficencia Portuguesa, São Paulo, Brazil

Professor Corey Casper
Global Health, Seattle, WA,
United States

Professor Seok-Goo Cho
Director of Cell Therapy Center, Seoul St. Mary’s Hospital, Seoul, Korea

Assistant Professor David Fajgenbaum
University of Pennsylvania, Perelman School of Medicine, Pennsylvania, United States

Professor Simon Harrison
Director, Centre of Excellence for Cellular Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Assistant Professor Sudipto Mukherjee
Director of Rare Cancers and Blood Diseases, Lerner College of Medicine at CWRU, Cleveland Clinic, Cleveland, Ohio, United States

Professor Eric Oksenhendler
Hôpital St Louis / Université Paris-Diderot, Paris, France

Associate Professor Karthik Ramasamy
University Of Oxford & Oxford University Hospitals NHS Trust, Oxford, United Kingdom

Professor Goh Yeow Tee
Senor Consultant, Singapore General Hospital, Singapore

Professor Frits Van Rhee
University of Arkansas for Medical Sciences Myeloma Centre, United States

Associate Professor Lu Zhang
Peking Union Medical College Hospital, Peking, China

Professor Pier Luigi Zinzani
Lymphoma and Chronic Lymphoproliferative Syndromes Unit Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Italy

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