The Combined Assessment of Function and Survival (CAFS): A new endpoint for ALS clinical trials

Berry, James; Miller, Robert G.; Moore, Dan H.; Cudkowicz, Merit; Berg, Leonard H. van den; Kerr, Douglas A.; Dong, Yan; Ingersoll, Evan W.; Archibald, Donald

doi:10.3109/21678421.2012.762930

Cited by 98 publications

(98 citation statements)

References 21 publications

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“…To incorporate functional outcomes in addition to survival, we utilized an ALSFRS‐R/survival composite measure (ALS/SURV), a novel analysis method that is a simplification of the combined assessment of function and score (CAFS) algorithm 22. In this method, all participants are ranked at each time point by ALSFRS‐R or time to death, allowing calculation of meaningful confidence intervals in terms of ALSFRS‐R score and/or length of survival.…”

Section: Methodsmentioning

confidence: 99%

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Goutman

Brown

Glass

et al. 2018

Ann Clin Transl Neurol

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ObjectiveIntraspinal human spinal cord‐derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb‐onset ALS participants in Phase 1 and 2 (Ph1/2) open‐label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs.MethodsSurvival, ALSFRS‐R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS‐R) functional status were assessed for matched participant subsets: PRO‐ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20.ResultsSurvival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO‐ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS‐R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO‐ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO‐ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS‐Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO‐ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study.InterpretationComparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO‐ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery‐controlled efficacy study.

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Section: Methodsmentioning

confidence: 99%

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Goutman

Brown

Glass

et al. 2018

Ann Clin Transl Neurol

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“…Combined Assessment of Function and Survival borrows its premise from similar analyses used in HIV trials, and has the potential to offer a more comprehensive view of a therapy's effect. It was used in a 2-part phase II study of dexpramipexole (KNS-760704) in ALS [68], and may have future applications in later-phase trials of ALS, having been accepted by the Food and Drug Administration for registration trials [81,82]. The analysis performs most robustly when a substantial number of survival events are expected during the trial.…”

Section: Confirmatory Phasementioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

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The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

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“…A novel solution to this quandary, the Combined Assessment of Function and Survival (CAFS [24]) (Fig. 6), has recently been utilized in a phase 2 and then a large phase 3 study in ALS [25,26].…”

Section: Motor Neuron Diseases: Clinical Trial Measures In Amyotrophimentioning

confidence: 99%

Commonalities and Challenges in the Development of Clinical Trial Measures in Neurology

et al. 2015

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As neurologists and neuroscientists, we are trained to evaluate disorders of the nervous system by thinking systematically. Clinically, we think in terms of cognition, behavior, motor function, sensation, balance and co-ordination, and autonomic system function. But when we assess symptoms of neurological disorders for the purpose of drug development, we tend to create disease-specific outcome measures, often using a variety of methods to assess the same types of dysfunction in overlapping, related disorders. To begin to explore the potential to simplify and harmonize the assessment of dysfunction across neurological disorders, a

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The Combined Assessment of Function and Survival (CAFS): A new endpoint for ALS clinical trials

Cited by 98 publications

References 21 publications

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

Commonalities and Challenges in the Development of Clinical Trial Measures in Neurology

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