Behçet Disease Clinical Trial
Official title:
Development and Preliminary Validation of the Behçet's Disease Overall Damage Index
Damage in vasculitis, as well as in other chronic inflammatory disorders, accrues over time
resulting in impairment of quality of life, development of disability and increased
mortality. For these reasons, damage represents an important outcome to be assessed and
measured both in trials and clinical practice.
Currently, the most widely used assessment tool for damage in vasculitis is the Vasculitis
Damage Index (VDI). However, VDI was developed for a no specific type of vasculitis and it
appears to be more suitable for damage assessment in ANCA-associated vasculitis than in
Behçet' disease (BD).
BD is a chronic and multisystem inflammatory disorder classified among vasculitides. As well
as in other vasculitides, disease activity and treatment in BD can result in the development
and accumulation of irreversible organ damage, such as blindness, tissue loss and a wide
range of neurologic disorders. Recently the OMERACT has defined the Core Set domain of
Outcome Measures for BD. Despite damage is included in the OMERACT outcome core set for
rheumatic disease, a specific assessment tool for BD is currently not available.
The aim of this study is to develop and validate the first tool for describing and measuring
organ damage in patients with Behçet Disease (Behçet's disease Overall Damage index - BODI).
DESIGN OF THE STUDY
This observational multicenter study will be developed in 2 subsequent phases, in their turn,
consisting of different steps (figure 1):
1. BODI Development 1.1) Development of a preliminary version of BODI (p-BODI) based on
literature review and inspired by pre-existing tools according to OMERACT guidelines;
1.2) Delphi process aimed to review and improve the p-BODI.
2. Validation of the new tool according to OMERACT filter 2.0 2.1) Application of the BODI
on a multicentre cohort of BD patients. 2.2) Assessment of face, content, construct and
criterion validity, and sensitivity to change.
2.3) Assessment of reliability based on scoring exercise on clinical vignettes.
All subjects involved in the study are experts in the management of BD. They will work in two
different groups having different roles:
- Work and facilitator group (WFG): consisting of 3 Physician from the Coordinating
Centre. The tasks of the WFG are: (a) to review literature and develop a preliminary
version of BODI (p-BODI), including: definition of damage, rules for scoring and
identification of potential items of damage; (b) to coordinate the Delphi process for
editing and optimizing p-BODI; (c) to analyse data from the validation process.
- Expert Panel (EP): consisting of multidisciplinary experts in Behçet's disease and
Patient's delegate from different countries. EP members will be selected and invited to
participate in the study by the WFG. The tasks of the EP are to express their opinion on
p-BODI and propose editing for its improvement within a Delphi process;
- Clinicians group (CG): consisting of one Clinician from each Centre, with expertise in
Behçet's disease but not involved in the Delphi process. The tasks of this group are:
(a) to apply the BODI on 30 consecutive patients with BD (10 for Neurologist and
Ophthalmologist) from each Centre involved in the study; (b) to score a set of clinical
vignettes using the BODI, to assess reliability of the instrument; (c) to express an
overall judgement (in an online survey) regarding to general credibility,
comprehensiveness and feasibility of the BODI.
The member of EP and GC, involved in the study so far, with respective affiliations, are
reported below:
EP members - CG members - Affiliations.
- Prof. Alessandro Mathieu - Dr. Matteo Piga - Chair and Unit of Rheumatology, University
and AOU of Cagliari, Monserrato - Italy;
- Prof. Govoni Marcello - Dr. Lo Monaco Andrea - Department of Medical Sciences, Section
of Rheumatology, AOU S. Anna, the University of Ferrara - Italy;
- Prof. Iannone Florenzo - Dr. Lopalco Giuseppe - Department of Emergency and Organ
Transplantation, Rheumatology Unit, University of Bari - Italy;
- Prof. Neri Piergiorgio - Dr. Pirani Vittorio - Ocular Immunology Service, the Eye
Clinic, Polytechnic University of Marche- Ancona - Italy;
- Prof. Cantarini Luca - Dr. Orlando Ida - Rheumatology Unit, University of Siena.
Policlinico Le Scotte;
- Prof. Martins Silva Ana - Dr. Santos Ernestina - Neurology Department, Hospital Santo
António, Centro Hospitalar do Porto - Portugal;
- Prof. Vasconcelos Carlos - Prof Correia Joao; Dr. Raquel Faria - Clinical Immunology
Unit, Centro Hospitalar do Porto and UMIB, ICBAS, Universidade do Porto, Portugal;
- Prof. Cervera Ricard - Dr. Espinosa Gerard, Dr. Ignasi Rodriguez - Department of
Autoimmune Diseases, Hospital Clinic, IDIBAPS, University of Barcelona - Spain;
- Prof. Bertsias George - Dr. Nikos Kougkas - Department of Rheumatology, Clinical
Immunology and Allergy, University of Crete School of Medicine - Grece;
- Patient Association delegates.
OPERATIVE STUDY DEVELOPMENT AND DATA ANALYSIS
1. BODI Development 1.1) Development of preliminary version of BODI (p-BODI) based on
literature review and inspired to pre-existing tools A preliminary list of damaged items
with respective definition will be generated after reviewing the literature and
preexisting damage indices (e.g VDI for vasculitides and SLICC damage index (SDI) for
systemic lupus erythematosus).
1.2) Reviewing and editing of the p-BODI by Delphi process A multi-step Delphi process,
based on reaching experts consensus, will be performed in order to review and refine the
p-BODI and the respective glossary. Through an online survey, each member EP will be
asked to rate: (a) how strongly they agree with the general rules for damage scoring;
(b) how strongly they agree to include the listed damage items within the BODI (e.g. to
which extent do you agree that "Cataract" should be included in the BODI?); (c) how
strongly they agree with the provided item definition. Ratings will be scored on a
5-point Likert scale (5 = strongly agree; 4 = agree; 3 = unsure; 2 = disagree; 1 =
strongly disagree). The EP members will be asked to give considerations and arguments to
support their opinion, especially if they score less than 4. They will also be given the
opportunity to suggest alternative wordings, to suggest additional items, or to make any
other comment.
In the reviewed p-BODI for the subsequent Delphi round, each issue (scoring rules,
damage items, item definitions) if: (a) ≥80% of EP members scores ≥4: will be included;
(b) 50-79% of EP members scores ≥4: will be included in the second questionnaire after
reviewing according to comments and suggestions provided in the previous round (c) <50%
of EP members scores: will be excluded.
The WFG has the right to make alternative decisions after reviewing the EP responses
(e.g propose to change an item definition according to a suggestion from the expert
panel, even if the item was scored >4 by ≥80% of EP).
An anonymous feedback report will be provided with the second questionnaire, in order to
offer the opportunity to reconsider and, if appropriate, to change a previous opinion in
light of the anonymous responses and considerations of the other EP members. The panel
members will again be asked to give their opinion on each issue in subsequent rounds
until complete consensus will be achieved (all issues scored ≥4 by ≥80% of EP) and the
definitive version of BODI will be developed.
2. Validation of BODI 2.1) Application of BODI on a multi-center cohort of BD patients Each
CG member will be asked to apply the reviewed version of BODI on a cohort of 30 BD
patients consecutively assessed in their own center. For Neurologist and
Ophthalmologist, the data from 10 consecutive patients will be enough. This is because
Neurologist and Ophthalmologist usually take care of the most severe neuropsychiatric
and ocular cases, which might bias the real prevalence of these manifestations in the
study cohort.
A multicenter cohort consisting of 200-250 BD patients will be thus set up. Patients will
undergo a routine clinical assessment, as scheduled in their follow-up program. No further
clinical, laboratory or instrumental investigations will be performed in addition to those
provided according to the good clinical practice. Any possible drug administration will be
evaluated independently from the study and according to the good clinical practice.
Inclusion criteria will be: a) BD diagnosis according to ICBD criteria, b) disease duration
≥12 months), c) age at enrolment ≥ 18 years. For each recruited patient data will be
anonymously collected at the enrolment visit (T0). For patients with more than 5 years of
follow-up at the enrollment time, investigators will be further asked to perform a 5 years
retrospective BODI (Tr5). The following data will be collected (see the attached Case Report
Form):
- T1: demographics and medical history (gender; birthday, onset, diagnosis and enrolment
date; country of origin; ethnicity; comorbidity; smoker status); cumulative clinical
manifestation from onset to enrolment (oral aphthosis, genital aphthosis, skin lesions,
ocular involvement, neurologic lesions, vascular lesions, pathergy test, arthritis,
gastrointestinal manifestations); active clinical manifestations the enrolment visit; ongoing
and past therapy; BD current activity form (BDCAF); BODI; VDI; Physician global assessment
(PGA)on visual analogic scale; Patients global assessment (PtGA) on visual analogic scale;
Short Form 36 (SF-36) Health Survey,
• Tr5 (retrospectively): BODI
2.2) Assessment of face, content, construct, criterion validity and sensitivity to change
Validation will be performed according to the principles of OMERACT Filter 2.0, thus
according to the criteria of (A) truth, (B) discrimination and (C) feasibility will be
assessed.
A.1. Face validity. Since BODI will be developed through literature review and consensus
between an expert in BD management, face validity criteria should be automatically met.
However, face validity will be further tested by asking each CG member to complete a
questionnaire investigating the suitability of the tool.
A.2. Content validity. To assure content validity, the presence of damage identified by CG
but not classifiable in BODI will be assessed. Content validity will be further tested by
asking each CG member to complete a questionnaire relating to the comprehensiveness of the
instrument.
A.3. Construct validity. It will be assessed analyzing the agreement between results of
damage assessment on our validation cohort by BODI and other damage assessment tool. Since
there are no other specific and validate instruments for damage amassment in Behçet disease,
SLICC and VDI will be used as a surrogate. Correlation between the different indices results
will be evaluated by Pearson's or Spearman's correlation coefficients.
A.4. Criterion Validity. Criterion validity represents the correlation with results of
measurement with the new tool and other long-term outcomes related to the phenomenon we are
measuring. Since we expect that damage correlates with quality of life, disability and
mortality, a correlation between BODI score and SF-36, HAQ and in the future also with
mortality rate will be assessed.
B.1. Reliability. Clinical vignettes will be created from real cases to test the reliability
of the BODI. Thus, inter-observer agreement (kappa) will be assessed by asking a physician
from every center to assess the same clinical vignettes.
B.2. Sensitivity to change. The ability of the BODI to record the accumulation of damage over
time will be examined by determining the change in BODI score over 5 years of follow-up on
the validation cohort. The average increase of BODI score from T1 to T2 will be calculated
and will be tested by the Mann-Whitney test.
C. Feasibility. To test feasibility each CG member will be asked to complete a questionnaire
relating to the ease of use, consumption of time and interpretability of the instrument.
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