https://orcid.org/0000-0002-7692-2189
Abstract
Aims
To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving reldesemtiv versus placebo in FORTITUDE-ALS.
Materials and methods
We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated reldesemtiv in patients with ALS. Health utilities from the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) were estimated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores collected during the trial. QALYs were estimated using the area under the curve method.
Results
The full analysis set consisted of 456 patients (reldesemtiv n = 342, placebo n = 114), who received at least one dose of the double-blind study drug, and had ALSFRS-R assessed at baseline and at least one post-baseline assessment. The difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% confidence interval [CI]: 0.01, 0.05; p = .0008). The incremental QALY of reldesemtiv versus placebo adjusted for baseline utility values showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058).
Conclusions
This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings.
ClinicalTrials.gov identifier
NCT03160898
Introduction
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects both upper and lower motor neuronsCitation1–4. ALS is clinically heterogeneous with variability in site of onset, age of onset, upper motor neuron or lower motor neuron signs and symptoms, the rate of disease progression, and survivalCitation1,Citation3. Typically, death occurs within three to five years from disease onset, most often due to respiratory paralysisCitation5.
The ALS Functional Rating Scale-Revised (ALSFRS-R) is considered the standard for assessment of disease progression in both clinical practice and randomized clinical trials in ALSCitation3,Citation6. The ALSFRS-R is a multidimensional scale that includes 12 items covering four domains (bulbar, lower limb, upper limb, and respiratory), with each item scored 0 (no function) through 4 (no deficit)Citation7.
Reldesemtiv is a fast skeletal muscle troponin activator, which acts by increasing muscle force generationCitation8. It is currently being investigated in a Phase III clinical trial for the treatment of ALS.
FORTITUDE-ALS was a Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial of reldesemtiv in patients with ALSCitation8. The trial was designed to assess the safety, tolerability, and potential efficacy of three dose levels of reldesemtiv versus placebo. Slow vital capacity (SVC) was the primary outcome measure and ALSFRS-R total score was a key secondary measure. When the three dose groups were assessed separately versus placebo, the primary efficacy analysis of change from baseline to week 12 in SVC was not statistically significant. However, in post hoc analyses comparing all doses of reldesemtiv combined versus placebo, reldesemtiv appeared to slow the decline in the ALSFRS-R total score by 25%, with nominal statistical significance (p = .01)Citation8. The main purpose of the current study was to estimate the effect of reldesemtiv on health utilities and quality-adjusted life years (QALYs) compared with placebo during the trial period.
Materials and methods
Clinical trial overview
The FORTITUDE-ALS (ClinicalTrials.gov identifier: NCT03160898) study design, including eligibility criteria, patient characteristics, and results, has been published previouslyCitation8. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.
Briefly, eligible patients with ALS were randomized 1:1:1:1 to receive either reldesemtiv oral tablets 150, 300, or 450 mg or placebo, dosed twice daily for 12 weeks. ALSFRS-R total score was assessed during screening, at day 1, and weeks 2, 4, 8, 12, and follow-up.
Data collection
For this analysis, data from all three reldesemtiv doses (150, 300, or 450 mg, twice daily) were pooled. Analyses were conducted on data from the full analysis set from FORTITUDE-ALS, which included all patients who received at least one dose of the double-blind study drug, had an efficacy assessment at baseline, and at least one post-baseline assessment. We also reported separate analyses of the three doses of reldesemtiv versus placebo to determine if the results were consistent with the pooled analysis.
Analysis
Health utilities from EQ-5D-5L were calculated for baseline and weeks 2, 4, 8, and 12. As EQ-5D-5L was not administered in FORTITUDE-ALS, EQ-5D-5L utility was estimated from the ALSFRS-R using a published mapping algorithmCitation9. The algorithm uses a linear regression model with five of the 12 items of the ALSFRS-R to estimate the EQ-5D-5L utilities (EQ-5D-5L utility = 0.086203 + 0.057486 × item 6 [dressing and hygiene] + 0.046674 × item 7 [turning in bed and adjusting bed clothes] + 0.058688 × item 8 [walking] + 0.035927 × item 9 [climbing stairs] + 0.021126 × item 10 [dyspnea])Citation9, based on a published value set for EnglandCitation10. Changes in EQ-5D-5L utility index scores from baseline to each post-baseline visit up to week 12 were analyzed using a mixed model for repeated measures (MMRM) with the treatment, baseline utility values, baseline riluzole use, baseline edaravone use, pooled sites, visit, interaction of visit-by-treatment, and interaction of visit-by-baseline-utility-value as covariatesCitation11,Citation12. Analyses were based on available data, with no imputation for missing values. As previously reportedCitation8, one patient (in the placebo group) died during the 12-week treatment period; subsequent values for that patient were set to missing and were not included in the analyses. Subsequently, QALYs were calculated using the area under the curve, using the baseline, week 2, 4, 8, and 12 EQ-5D-5L utilitiesCitation13,Citation14. Where a utility value was missing, QALYs were estimated with available data; for example, if a week 8 utility value was missing, the QALY was estimated using linear interpolation between weeks 4 and 12. Incremental QALY adjusted for baseline utility values was estimated using a multiple linear regression modelCitation14,Citation15. We report the difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 and incremental QALY between reldesemtiv and placebo along with the 95% confidence interval (CI). Analyses were conducted using SAS version 9.4 or greater (SAS Institute, Cary, NC, USA).
Results
Patient demographics and clinical characteristics
A total of 456 patients who were randomized to receive either reldesemtiv (n = 342) or placebo (n = 114) were included in the analyses. Patient characteristics for the two treatment arms were well balanced between the reldesemtiv and placebo groups (), including the baseline ALSFRS-R total score (mean total score of 37.5 vs. 37.0, respectively).
Table 1. Baseline characteristics of patients with ALS in FORTITUDE-ALS.
EQ-5D-5L health utilities and QALYs
The majority of patients completed the 12-week treatment period; the number of patients with data available for analysis at each time point is shown in . At baseline, the mean EQ-5D-5L utilities for patients in the reldesemtiv and placebo groups were similar (0.67 vs. 0.64, respectively) (). The mean health utilities in both groups declined during the trial, but the decrement was smaller in the reldesemtiv group compared with placebo (). By the end of the trial, the decrement in EQ-5D-5L utility score was smaller in the reldesemtiv group compared with the placebo group (–0.06 vs. −0.09, respectively) after baseline adjustment. The difference in EQ-5D-5L utility LS mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% CI: 0.01, 0.05; p = .0008) (). For each dose of reldesemtiv versus placebo, trends were consistent with those of the pooled analysis ().
Table 2. EQ-5D-5L utility scores and QALY for reldesemtiv and placebo in FORTITUDE-ALS.
Table 3. Change from baseline in EQ-5D-5L at all visits.
Table 4. Change from baseline in EQ-5D-5L at all visits for reldesemtiv 150 mg BID and placebo in FORTITUDE-ALS.
Table 5. Change from baseline in EQ-5D-5L at all visits for reldesemtiv 300 mg BID and placebo in FORTITUDE-ALS.
Table 6. Change from baseline in EQ-5D-5L at all visits for reldesemtiv 450 mg BID and placebo in FORTITUDE-ALS.
The QALYs for reldesemtiv and placebo were 0.1639 and 0.1513, respectively (). The incremental QALY of reldesemtiv versus placebo, adjusted for baseline utility values, showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058) (). The incremental QALYs for each dose of reldesemtiv versus placebo were consistent with the results of the pooled analysis ().
Table 7. EQ-5D-5L utility scores and QALY for reldesemtiv 150 mg BID and placebo in FORTITUDE-ALS.
Table 8. EQ-5D-5L utility scores and QALY for reldesemtiv 300 mg BID and placebo in FORTITUDE-ALS.
Table 9. EQ-5D-5L utility scores and QALY for reldesemtiv 450 mg BID and placebo in FORTITUDE-ALS.
Discussion
The main objective of this study was to assess the effect of reldesemtiv on health utilities and QALYs compared with placebo during the trial period. Our results showed that at baseline the mean EQ-5D-5L utilities mapped from the ALSFRS-R for patients in the reldesemtiv and placebo groups were similar. While mean health utilities in both treatment arms declined over time, the decrement was smaller in the reldesemtiv group. Furthermore, the incremental QALY of reldesemtiv versus placebo showed a modest but significant difference. This analysis suggests that reldesemtiv may provide benefit in EQ-5D health utilities and QALYs compared with placebo, although this requires further confirmatory research.
ALS is a devastating disease that can lead to a significant decline in patients’ health-related quality of life (HRQoL) as the disease progresses. The EQ-5D is a preferred measure of HRQoL by the National Institute for Health and Care Excellence (NICE) in the United Kingdom and the Institute for Clinical and Economic Review (ICER) in the United StatesCitation16,Citation17. There are several published studies that reported the minimum important difference (MID) for EQ-5D, albeit based on the EQ-5D-3L, and difference index valuesCitation18. Overall, these previous studies found the MID for EQ-5D ranges from 0.03 to 0.52, with the wide range resulting from the use of EQ-5D in a variety of diseases with different levels of severityCitation18. MID represents the smallest amount of benefit that patients consider valuable. In our analyses of clinical trial data from FORTITUDE-ALS, we found patients with ALS who received reldesemtiv had a greater health utility, as assessed by the EQ-5D-5L, compared with those in the placebo group, with a significant difference of 0.03. This incremental health benefit of reldesemtiv falls within the reported ranges of the MID for EQ-5D-3L using the UK scoring algorithm.
We also assessed the impact of reldesemtiv versus placebo on QALYs in FORTITUDE-ALS. Reldesemtiv provides a modest and statistically significant difference of 0.004 QALY over placebo, equivalent to 1.5 days in perfect health when it is expressed in quality-adjusted life days (=QALY × 365 days) over the 12-week periodCitation19. Clearly, the shorter the trial period (or time horizon within an economic model), the smaller the QALY gainCitation20. Unfortunately, there is very little published information available for comparison in ALS. Recently, ICER reported a lifetime incremental QALY of 0.04 and 0.14 for two other ALS interventions, oral edaravone, and AMX0035, respectivelyCitation21. However, our analysis of QALY for reldesemtiv was based on data collected during 12 weeks and was not extrapolated over lifetime. Therefore, direct comparison of those QALYs is not appropriate.
Limitations
There are several limitations in our analysis. EQ-5D-5L utility values were estimated through mapping from the ALSFRS-R because EQ-5D-5L was not administered in the clinical trial. Thus, the quality of our results and conclusions may have been affected by the robustness of the mapping algorithm used to estimate the EQ-5D-5L utility values. The authors stated that the mapping results of the study fell within the reported mean squared errors ranges of other published mapping studies and asserted it is possible to derive EQ-5D-5L from ALSFRS-R with reasonable accuracyCitation9. In addition, none of the items of the ALSFRS-R are related to pain/discomfort or anxiety/depression, which are included in the EQ-5D-5L. It has been suggested that these items are usually reported in less severe terms by patients with ALSCitation9, but this can only be confirmed by the inclusion of EQ-5D-5L into a future placebo-controlled randomized trial. Another limitation is that the EQ-5D-5L value set for England is not recommended by NICE. However, there is an ongoing study to generate the EQ-5D-5L value set for the UK funded by EuroQol with advice from NICECitation22. Lastly, while this analysis has estimated QALYs over 12 weeks, within an economic analysis framework, the correct time horizon specification is lifetime, meaning that there is time horizon bias in the QALY estimates.
To the best of our knowledge, this is the first time that data from a randomized controlled trial have been applied to the published mapping algorithm developed by Moore et al.Citation9 to estimate utilities from the EQ-5D-5L from the ALSFRS-R. Our results suggest this mapping methodCitation9 (ALSFRS-R mapped to EQ-5D-5L) may be useful to show the treatment effect in terms of health utilities in clinical trials of ALS. The modest effect of reldesemtiv on QALYs is likely due to the three-month short-term trial period.
A strength of our analysis is the use of data from a randomized, placebo-controlled clinical trial, in which ALSFRS-R data were collected prospectively. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings.
Conclusions
This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALY compared with placebo in patients with ALS.
Transparency
Declaration of funding
FORTITUDE-ALS was conducted by Cytokinetics, Incorporated in collaboration with Astellas Pharma Inc.
Declaration of financial/other relationships
PG, LM, SAR, JW, AAW, and MB own stock and are employees of Cytokinetics, Incorporated. PS was an employee at the time of the FORTITUDE-ALS trial. AC serves on the advisory board for Biogen, Cytokinetics, Incorporated, D enali Pharma, Amylyx, and Mitsubishi Tanabe Pharma. JAA has received research funding to their institution from Alexion, AZTherapies, Amylyx, Biogen, Cytokinetics, Orion, Novartis, MGH Foundation, Ra Pharma, Biohaven, Clene, and Prilenia and consulting fees from AL-S. Affinia, Amylyx, Apellis, Biogen, Cytokinetics, Denali, Orphazyme, NeuroSense, Novartis, UCB, and Wave Life Sciences. AG has served as a consultant for AB Science, AL-S Pharma, AveXis, Biogen, Cytokinetics, Incorporated, Mitsubishi Tanabe Pharma America, and Roche. DAH has no conflicts of interest to declare. CEJ has served as a member of data safety monitoring boards for Anelixis Therapeutics, Inc. and Mitsubishi Tanabe Pharma America. NL has served as a consultant/advisor for Cytokinetics, Incorporated, Hill-Rom Services, Inc., and Vertex Pharmaceuticals Incorporated; and has received research support from AstraZeneca and Vertex Pharmaceuticals Incorporated. TMM has served as a consultant/advisor for Biogen, Ionis Pharmaceuticals, Disarm Therapeutics, and Cytokinetics, Incorporated; has received research support from Biogen and Ionis Pharmaceuticals; and receives licensing fees from Ionis Pharmaceuticals and C2N. JMS reports compensation received as a consultant from Amylyx, Apic Biosciences, NeuroSense Therapeutics, Cytokinetics, Incorporated, Denali Therapeutics, GSK, Mitsubishi Tanabe Pharma America, Orphazyme, Orthogonal, Pinteon Therapeutics, RRD, SwanBio, Helixmith, Novartis, Sanofi, PTC, and EMD Serono; and reports research support from Amylyx, Biogen, Biotie Therapies (now Acorda Therapeutics), Cytokinetics, Incorporated, Mitsubishi Tanabe Pharma America, Alexion, MediciNova Inc, Ionis, Alector, and Orphazyme. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
PG provided support with concept and design. PG, LM, and JW provided statistical analysis. PG and PS provided support with interpretation of data. PG drafted the manuscript. All authors provided critical revision/review of the paper, final approval of the version to be published, and agreed to be accountable for all aspects of the work.
Acknowledgements
We wish to thank the participants of FORTITUDE-ALS and their families for their contributions to this clinical trial, the investigators of FORTITUDE-ALS, the FORTITUDE-ALS Study Group, and members of the Data Monitoring Committee and Steering Committee. The authors acknowledge Emily Chu (Evidence Scientific Solutions, Horsham, UK), and Richard Fay (Evidence Scientific Solutions, Philadelphia, PA, USA), for editorial assistance, which was funded by Cytokinetics, Incorporated.
Data availability statement
The data reported herein are part of a sponsor-led clinical development program that is ongoing, thus complete datasets for the trial will not be made available with this report.
References
- Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162–172.
- Chiò A, Hammond ER, Mora G, et al. Development and evaluation of a clinical staging system for amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(1):38–44.
- Corcia P, Beltran S, Lautrette G, et al. Staging amyotrophic lateral sclerosis: a new focus on progression. Rev Neurol. 2019;175(5):277–282.
- Tramacere I, Dalla Bella E, Chiò A, et al. The MITOS system predicts long-term survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(11):1180–1185.
- Lechtzin N, Cudkowicz ME, de Carvalho M, et al. Respiratory measures in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19(5-6):321–330.
- Hartmaier SL, Rhodes T, Cook SF, et al. Qualitative measures that assess functional disability and quality of life in ALS. Health Qual Life Outcomes. 2022;20(1):12.
- Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS study group (phase III). J Neurol Sci. 1999;169(1-2):13–21.
- Shefner JM, Andrews JA, Genge A, et al. A phase 2, double-blind, randomized, dose-ranging trial of reldesemtiv in patients with ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2021;22(3-4):287–299.
- Moore A, Young CA, Hughes DA. Mapping ALSFRS-R and ALSUI to EQ-5D in patients with motor neuron disease. Value Health. 2018;21(11):1322–1329.
- Devlin NJ, Shah KK, Feng Y, et al. Valuing health-related quality of life: an EQ-5D-5L value set for England. Health Econ. 2018;27(1):7–22.
- Detry MA, Ma Y. Analyzing repeated measurements using mixed models. JAMA. 2016;315(4):407–408.
- Griffiths A, Paracha N, Davies A, et al. Analyzing health-related quality of life data to estimate parameters for cost-effectiveness models: an example using longitudinal EQ-5D data from the SHIFT randomized controlled trial. Adv Ther. 2017;34(3):753–764.
- Matthews JN, Altman DG, Campbell MJ, et al. Analysis of serial measurements in medical research. BMJ. 1990;300(6719):230–235.
- Manca A, Hawkins N, Sculpher MJ. Estimating mean QALYs in trial-based cost-effectiveness analysis: the importance of controlling for baseline utility. Health Econ. 2005;14(5):487–496.
- Xin Y, Ashburn A, Pickering RM, et al. Cost-effectiveness of the PDSAFE personalised physiotherapy intervention for fall prevention in Parkinson’s: an economic evaluation alongside a randomised controlled trial. BMC Neurol. 2020;20(1):295.
- National Institute for Health and Care Excellence. Position statement on use of the EQ-5D-5L value set for England (updated October 2019) [Internet]. 2019 [accessed 2022 July 8]. Available from: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/technology-appraisal-guidance/eq-5d-5l
- Institute for Clinical and Economic Review. Value assessment framework [Internet]. 2020 [accessed 2022 July 8]. Available from: https://icer.org/our-approach/methods-process/value-assessment-framework/
- Coretti S, Ruggeri M, McNamee P. The minimum clinically important difference for EQ-5D index: a critical review. Expert Rev Pharmacoecon Outcomes Res. 2014;14(2):221–233.
- Goldfeld KS, Hamel MB, Mitchell SL. The cost-effectiveness of the decision to hospitalize nursing home residents with advanced dementia. J Pain Symptom Manage. 2013;46(5):640–651.
- Polak TB, Cucchi DGJ, Darrow JJ, et al. Incremental benefits of novel pharmaceuticals in the UK: a cross-sectional analysis of NICE technology appraisals from 2010 to 2020. BMJ Open. 2022;12(4):e058279.
- Makam AN, Suh K, Nikitin D, et al. AMX0035 and oral edaravone for ALS; final evidence report [Internet]. Institute for Clinical and Economic Review. 2022 Sept 1 [ accessed 2023 Jan 11]. Available from: https://icer.org/assessment/amyotrophic-lateral-sclerosis-2022/#timeline
- EuroQol Research Foundation. New UK EQ-5D-5L valuation study [Internet]. 2022 [accessed 2022 July 8]. Available from: https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-sets/new-uk-eq-5d-5l-valuation-study_blog/