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. 2024 Nov 14;14(11):e085234.
doi: 10.1136/bmjopen-2024-085234.

Identifying thresholds for meaningful improvements in NTDT-PRO scores to support conclusions about treatment benefit in clinical studies of patients with non-transfusion-dependent beta-thalassaemia: analysis of pooled data from a phase 2, double-blind, placebo-controlled, randomised trial

Ali T Taher  1 , Khaled M Musallam  2   3 , Vip Viprakasit  4 , Antonis Kattamis  5 , Jennifer Lord-Bessen  6 , Aylin Yucel  6 , Shien Guo  7 , Christopher G Pelligra  8 , Alan L Shields  9 , Jeevan K Shetty  10 , Mrudula B Glassberg  11 , Luciana Moro Bueno  10 , Maria Domenica Cappellini  12
Affiliations

Identifying thresholds for meaningful improvements in NTDT-PRO scores to support conclusions about treatment benefit in clinical studies of patients with non-transfusion-dependent beta-thalassaemia: analysis of pooled data from a phase 2, double-blind, placebo-controlled, randomised trial

Ali T Taher et al. BMJ Open. .

Abstract

Objectives: To estimate thresholds for defining meaningful within-patient improvement from baseline to weeks 13-24 and interpreting meaningfulness of between-group difference for the non-transfusion-dependent beta-thalassaemia patient-reported outcome (NTDT-PRO) tiredness/weakness (T/W) and shortness of breath (SoB) scores. A secondary objective was to determine the symptom severity threshold for the NTDT-PRO T/W domain to identify patients with symptomatic T/W.

Design: Pooled blinded data from the phase 2, double-blind, placebo-controlled, randomised BEYOND trial in NTDT (NCT03342404) were used. Anchor-based analyses supplemented with distribution-based analyses and empirical cumulative distribution function (eCDF) curves were applied. Distribution-based analyses and receiver operating characteristic curves were used to estimate between-group difference and symptomatic thresholds, respectively.

Setting: Greece, Italy, Lebanon, Thailand, the UK and the USA.

Participants: Adults (N=145; mean age 39.9 years) with NTDT who were transfusion-free ≥8 weeks before randomisation.

Measures: Score changes from baseline to weeks 13-24 in PROs used as anchors (correlation coefficient ≥0.3): NTDT-PRO T/W and SoB scores, Patient Global Impression of Severity, Functional Assessment of Chronic Illness Therapy-Fatigue (Fatigue Subscale, item HI12 and item An2) and Short Form Health Survey version 2.

Results: The eCDF curves support the use of estimates from the improvement by one level group for all anchors to determine the threshold(s) for meaningful within-patient improvement. Mean (median) changes from these groups and estimates from distribution-based analyses suggest that a ≥1-point reduction in the NTDT-PRO T/W or SoB domains represents a clinically meaningful improvement. Meaningful between-group difference threshold ranges were 0.53-1.10 for the T/W domain and 0.65-1.15 for the SoB domain. The optimal symptomatic threshold for the T/W domain (by maximum Youden's index) was ≥3 points.

Conclusions: The thresholds proposed may support the use of NTDT-PRO in assessing and interpreting treatment effects in clinical studies and identifying patients with NTDT in need of symptom relief.

Keywords: Fatigue; HAEMATOLOGY; Patient Reported Outcome Measures.

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Conflict of interest statement

Competing interests: ATT has received consulting fees and research funding from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, Ionis Pharmaceuticals, Novartis Pharmaceuticals and Vifor Pharma. KMM has received consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Novartis, Pharmacosmos and Vifor Pharma; research funding from Agios Pharmaceuticals and Pharmacosmos. VV has received research funding from Bristol Myers Squibb. AK has received advisory board fees and consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, Chiesi Farmaceutici, CRISPR Therapeutics/Vertex Pharmaceuticals, Ionis Pharmaceuticals, Novartis and Vifor Pharma; research support from Celgene/Bristol Myers Squibb and Novartis. JL-B, AY, MBG and LMB are employed by and are stock/equity holders of Bristol Myers Squibb. SG is employed by Evidera; has received consultancy fees from Bristol Myers Squibb, Gilead and Janssen. CGP is employed by Evidera. ALS is employed by Adelphi Values. JKS was formerly employed by and is currently a stock/equity holder of Bristol Myers Squibb. MDC has received advisory board fees from Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Sanofi Genzyme and Vifor Pharma.

Figures

Figure 1
Figure 1. eCDF curves of changes in NTDT-PRO T/W domain scores from baseline to weeks 13–24 by level of response on different anchors. *For the PGI-S, worsening, no change, improvement by 1 level, by 2 levels, by 3 levels and by ≥4 levels were defined as a change of ≥1, >−1 to <1, >−2 to ≤−1, >−3 to ≤−2, >−4 to ≤−3 and ≤−4 points, respectively. †For the FACIT-F FS, worsening, no change, improvement by 1 level and by 2 levels were defined as a change of ≤−4, >−4 to <4, ≥4 to <8 and ≥8 points, respectively. ‡For FACIT-F items HI12 and An2, worsening, no change, improvement by 1 level and by 2 levels were defined as a change of ≤−1, >−1 to <1, ≥1 to <2 and ≥2 to <3 points, respectively. §For SF-36v2 vitality, worsening, no change, improvement by 1 level and by 2 levels were defined as a change of ≤−6.7, >−6.7 to <6.7, ≥6.7 to <13.4 and ≥13.4 points, respectively. eCDF, empirical cumulative distribution function; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; FS, Fatigue Subscale; NTDT-PRO, non-transfusion-dependent beta-thalassaemia patient-reported outcome; PGI-S, Patient Global Impression of Severity; SF-36v2, Short Form Health Survey version 2; T/W, tiredness/weakness.
Figure 2
Figure 2. eCDF curves of changes in NTDT-PRO SoB domain scores from baseline to weeks 13–24 by level of response on different anchors. *For the PGI-S, worsening, no change, improvement by 1 level, by 2 levels, by 3 levels and by ≥4 levels were defined as a change of ≥1, >−1 to <1, >−2 to ≤−1, >−3 to ≤−2, >−4 to ≤−3 and ≤−4 points, respectively. †For the FACIT-F FS, worsening, no change, improvement by 1 level and by 2 levels were defined as a change of ≤−4, >−4 to <4, ≥4 to <8 and ≥8 points, respectively. ‡For FACIT-F items HI12 and An2, worsening, no change, improvement by 1 level and by 2 levels were defined as a change of ≤−1, >−1 to <1, ≥1 to <2 and ≥2 to <3 points, respectively. §For SF-36v2 vitality, worsening, no change, improvement by 1 level and by 2 levels were defined as a change of ≤−6.7, >−6.7 to <6.7, ≥6.7 to <13.4 and ≥13.4 points, respectively. eCDF, empirical cumulative distribution function; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; FS, Fatigue Subscale; NTDT-PRO, non-transfusion-dependent beta-thalassaemia patient-reported outcome; PGI-S, Patient Global Impression of Severity; SF-36v2, Short Form Health Survey version 2; SoB, shortness of breath.
Figure 3
Figure 3. ROC analysis to identify a symptomatic threshold for the NTDT-PRO T/W domain score. FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; FS, Fatigue Subscale; NTDT-PRO, non-transfusion-dependent beta-thalassaemia patient-reported outcome; ROC, receiver operating characteristic; SF-36v2, Short Form Health Survey version 2; T/W, tiredness/weakness.
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