Supplementary Material
Development of a Patient-reported Outcome Measure for a Rare Disease: The Multicentric
Castleman’s Disease–Symptom Scale (MCD-SS)
Objective
To develop and validate an MCD-SS to accurately assess patient-reported symptoms of multicentric
Castleman’s disease (MCD).
Methods
The MCD-SS was developed following the US Food and Drug Administration patient-reported outcome
(PRO) guidance.1
Results
MCD-SS Scoring
Scoring was summarized by domain: Fatigue (tiredness, fatigue, lack of energy, feeling weak),
Rash/Itching (sores/rash on skin, itch), and Sweats (night sweats, daytime sweats), plus a total score
(Figure 1). The remaining symptoms (i.e., cough, shortness of breath, loss of appetite, numbness or
tingling, pain, swollen lymph nodes, and swelling or edema) were not categorized to a specific domain;
fever was excluded, as it could be assessed through other objective measures, such as measurement of
body temperature.
Figure 1. MCD-SS conceptual framework.
MCD-SS, Multicentric Castleman’s Disease–Symptom Scale.
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Patients rated their symptom severity from 0 to 5 (Table 1).
Domain scores and total score were rescaled to a range of 0 to 10, with higher scores representing
greater symptom severity. Domain scores and the remaining individual items were summarized to
generate a total score (below). Reductions in MCD-SS scores over time indicate improvements in MCDrelated symptoms.
Three domain scores and a total symptom score were computed from the individual items as follows:
•
FATIGUE = [2 * (Q4 + Q5 + Q6 + Q7)] / 4
•
RASH/ITCHING = [2 * (Q8 + Q9)] / 2
•
SWEATS = [2 * (Q15 + Q16)] / 2
•
TOTAL SCORE = [2 * (Q1 + Q2 + Q3 + Q10 + Q11 + Q13 + Q14) + FATIGUE + RASH/ITCHING +
SWEATS] / 10
FATIGUE ITEMS: Q4 Tiredness; Q5 Fatigue; Q6 Lack of energy; Q7 Feeling weak.
RASH/ITCHING ITEMS: Q8 Sores/rash on skin; Q9 Itching.
SWEATS ITEMS: Q15 Night sweats; Q16 Daytime sweating.
OTHER ITEMS: Q1 Cough; Q2 Shortness of breath; Q3 Loss of appetite; Q10 Numbness or tingling; Q11 Pain; Q13
Swollen lymph nodes; Q14 Swelling or edema.
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Assessment of Reliability and Validity
Test-retest reliability (intraclass correlation coefficients) exceeded the accepted threshold of 0.70 for
Fatigue and Sweats, as well as the total score, but was lower for Rash/Itching (r = 0.65). Cronbach’s
coefficient alpha based on standardized variables was 0.78 for the total score and, for the 3 subscales,
was 0.94, 0.87, and 0.71 for Fatigue, Rash/Itching, and Sweats, respectively. Known-groups validity was
evaluated against the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale (Table 2).
Subjects with ECOG scores of 0, 1, or 2 were enrolled in this study. MCD-SS scores followed the expected
pattern for ECOG grades, with the lowest MCD-SS scores associated with the lowest ECOG grades and
increasing as ECOG grade increased for Fatigue, Sweats, and total score.
Convergent validity was evaluated against the Functional Assessment of Chronic Illness Therapy–Fatigue
(FACIT-Fatigue) scale and Medical Outcome Study Short-Form 36 (SF-36) instrument (Table 3). MCD-SS
total score was moderately correlated with the clinician-reported, MCD-related signs and symptoms
index score at baseline (r = 0.48).
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Correlation between the MCD-SS total score and FACIT-Fatigue score was higher (r = –0.70), in part,
because there was a higher level of endorsement of severity of the Fatigue domain among respondents
than any other symptom included in the MCD-SS, confirming that fatigue is a key symptom of MCD.
MCD-SS domain scores and individual MCD clinician-rated signs and symptoms were moderately
correlated.
Ability of MCD-SS to Detect Change
MCD-SS measurements were recorded during the MCD2001 clinical study, where the efficacy of
siltuximab was compared with placebo in patients with MCD. An example of the change over time in the
MCD-SS fatigue score is shown in Figure 2. Patients treated with siltuximab reported early and
significantly greater improvements in fatigue severity compared with patients in the placebo group
(P = 0.02) showing that the MCD-SS was able to detect change over time.
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Figure 2. Change in mean MCD-SS fatigue scores over time.
MCD-SS, Multicentric Castleman’s Disease–Symptom Scale.
Conclusions
The MCD-SS is the first PRO instrument designed to assess symptom severity in MCD patients and,
consistent with the literature, fatigue was identified as the key symptom for patients with MCD. MCD
patients treated with siltuximab, an anti–interleukin (IL)-6 monoclonal antibody, demonstrated early
and consistent improvement in MCD-SS fatigue scores compared with patients receiving placebo.
Overall, our findings demonstrate that the MCD-SS is a reliable and valid tool to evaluate patientreported MCD symptoms in the clinical setting, and has the ability to detect responses after therapeutic
intervention.
References
1. US Department of Health and Human Services.
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. Accessed January 23, 2014.
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