Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 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
Clinical Trial

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.

PubMed Disclaimer

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.
See this image and copyright information in PMC

References

    1. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11. doi: 10.1186/1750-1172-5-11. - DOI - PMC - PubMed
    1. Taher A, Musallam K, Cappellini MD. Thalassaemia International Federation Nicosia (Cyprus)©. 3rd. 2023. [22-Feb-2023]. Guidelines for the management of non transfusion dependent thalassaemia (NTDT)https://thalassaemia.org.cy/publications/tif-publications/guidelines-for... edn. Available. Accessed. - PubMed
    1. Taher AT, Radwan A, Viprakasit V. When to consider transfusion therapy for patients with non-transfusion-dependent thalassaemia. Vox Sang. 2015;108:1–10. doi: 10.1111/vox.12201. - DOI - PMC - PubMed
    1. Vichinsky E. Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology, complications, and management. Curr Med Res Opin. 2016;32:191–204. doi: 10.1185/03007995.2015.1110128. - DOI - PubMed
    1. Musallam KM, Rivella S, Vichinsky E, et al. Non-transfusion-dependent thalassemias. Haematologica. 2013;98:833–44. doi: 10.3324/haematol.2012.066845. - DOI - PMC - PubMed

Publication types

LinkOut - more resources