Outcomes and interventions in clinical studies investigating pharmacological therapies for the treatment of transthyretin
amyloidosis: a targeted review
Alsawady M & Borecka O Vitaccess, London, UK
Background & Objectives
Transthyretin amyloidosis (ATTR) is a rare, progressive disease characterised by the abnormal accumulation of transthyretin protein in tissues and organs1 . This accumulation leads to organ dysfunction, impacting various bodily systems such as the nervous and cardiovascular systems2
The progression of ATTR can result in debilitating symptoms such as severe neuropathy, heart failure, gastrointestinal dysfunction, and renal impairment, all of which significantly reduce quality of life (QoL) for affected individuals, imposing limitations on daily activities, causing emotional distress, and compromising independence and overall wellbeing2 3
As pharmaceutical therapies for ATTR continue to evolve, it becomes crucial to comprehensively understand the interventions and outcomes assessed in clinical trials to evaluate their effectiveness in managing the disease progression and improving patient outcomes This review aimed to identify and categorise the outcomes and interventions used in clinical trials investigating pharmaceutical therapies for the treatment of ATTR
Methods
A targeted search of ClinicalTrials gov was conducted for phase 2, 3 and 4 studies marked as ‘recruiting’ and ‘active, not recruiting’ at the time of data extraction (February 2024). Study titles and overviews were screened to identify relevant trials. All studies investigating ATTR, including wild-type, variant, and hereditary forms, were included in this review.
Data on study design, intervention details, patient-reported outcome measures (PROMs), and clinical outcome assessments (COAs) were extracted Two independent reviewers cross-checked the extracted data to ensure accuracy and resolve any discrepancies through discussion
Results
The review included 15 studies, comprising 2 in Phase 2, 10 in Phase 3, and 3 in Phase 4 Among these, 8 studies were marked as ‘active, not recruiting’, while 7 were listed as ‘recruiting’ The sample sizes (actual or estimated) varied, ranging from 22 participants to 1,438, with a mean of 378 participants (Table 1)
Table 1 Overview of studies included in the review
A total of 11 different therapies for ATTR were investigated across the studies
The top three were eplontersen (27%), vutrisiran (13%) and patisiran (13%)
A total of five PROMs were included in the studies; three were specific to the symptoms of the disease itself, while the remaining two were generic (SF-36 and EQ-5D-5L) As shown in Figure 1, the most frequently used PROMs were the KCCQ (73%; n=8) and the Norfolk QOL-DN (27%; n=3) PROMs were included in 73% (n=11) of studies
A total of 25 COAs were included in 93% (n=14) of studies As shown in
Figure 2, the most frequently used COAs were gait speed walk test (57%; n=8), all-cause mortality (43%; n=6) and treatment-emergent adverse events (36%; n=5).
Figure 2 Top 12 COAs used across the studies reviewed CV=cardiovascular, NIS=neuropathy impairment score, R-ODS=Rasch-built overall disability scale, ECG=electrocardiogram, mBMI=modified body mass index, AEs=adverse events
Discussion & Conclusions
The findings of this review suggest that while a range of interventions and outcomes for ATTR have been explored, there is ongoing scope for more comprehensive assessments to further understand their efficacy This review serves as a foundational piece, highlighting areas that merit further exploration The prevalence of gait speed walk tests and all-cause mortality as endpoints emphasises the focus on functional and survival outcomes While all PROMs inherently measure patients’ QoL, the predominant use of the KCCQ specifically underscores its utility and relevance in this context Additionally, the diversity in pharmacological interventions signals an evolving treatment landscape, with eplontersen emerging as a notable candidate
Capturing patient perspectives and assessing QoL is indispensable for enhancing patient outcomes and deepening medical comprehension Hence, it is imperative for future studies to continue incorporating PROMs to fully capture treatment impact, thereby enhancing patient-centred care in the treatment and management of ATTR
References
1. Jain A, Zahra F Transthyretin Amyloid Cardiomyopathy (ATTR-CM) StatPearls Publishing; 2023
2. Carroll A, Dyck PJ, de Carvalho M, et al Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis J Neurol Neurosurg Psychiatry 2022;93(6):668-678 doi:10 1136/jnnp-2021-327909
3. Rintell D, Heath D, Braga Mendendez F, et al Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups Orphanet J Rare Dis 2021;16(1) doi:10 1186/s13023-021-01706-7
Note: The full list of studies reviewed as part of this study is available upon request Please contact Malak Alsawady@vitaccess com for further information
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Figure 1 Percentage of PROMs used across the studies reviewed