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

Figures & data

Table I. Examples of published composite endpoints and analyses for clinical trials.

Year	Analyses/Outcomes included
1984 (12)	Non-parametric and parametric approaches to analyzing multiple endpoints; illustrated using a diabetes trial
1999 (15)	Non-parametric evaluation of time to event (e.g. mortality) and longitudinal measure (e.g. change over time in CD4 lymphocyte count in HIV/AIDS)
2000 (16)	Analysis of longitudinal measure and event history or survival; illustrated using a schizophrenia trial
2006 (24)	Repeated measurements and event time data (shared parameter model)
2007 (13); 2011 (25)	Continuous measure over time (e.g. disability index in scleroderma) and time-to-event outcomes (e.g. renal crisis and death in scleroderma)
2007 (17)	Longitudinal measurement (e.g. change in percent forced vital capacity for scleroderma-associated lung disease) and time to treatment failure or death (in scleroderma-associated lung disease)
2008 (14)	Death and another outcome such as stroke, myocardial infarction, time to re-intervention, angina, or hospitalization in cardiovascular clinical trials
2010 (9)	Time to loss of virological response; incorporates virological failure assessments, loss to follow-up, new treatment initiation, and death

HIV: human immunodeficiency virus.

Figure 1. Example of the Combined Assessment of Function and Survival calculation using a hypothetical study with six patients. ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised.

Table II. Dexpramipexole phase II, part 2 study results (19).

Parameter	Dexpramipexole dose		Relative benefit in 300 mg vs. 50 mg groups	p-value
	50 mg (n =48)	300 mg (n = 44)
Mortality at 24 weeks, n (%)*	9 (18.8)	3 (7)	68%**	0.071
ALSFRS-R slope (units/month)	−1.28	−1.02	21%	0.177
CAFS, mean rank (range, 1–92^±)	41.1	52.4	27%	0.046

ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised; CAFS: Combined Assessment of Function and Survival.

^*Kaplan-Meier estimate.

^**Reduction in hazard ratio from Cox proportional hazards model.

^±Range depends on the number of patients in the study.

Table III. Power of EMPOWER study based on simulation of various hypothetical scenarios for outcome of ALSFRS-R and survival.

Case	Hypothetical scenario Percent improvement in		Power values for EMPOWER			Scenario interpretation
	ALSFRS-R slope	Mortality hazard	Slopes model	Survival (12 months)	CAFS
1	22	24	.95	.36	.91	Similar effects on ALSFRS-R and survival: CAFS has modestly less power than ALSFRS-R slope analysis because it is non-parametric. Non-parametric tests make fewer assumptions about underlying data and tend to be more conservative than parametric analyses (fewer false positives).
2a	21	50	.95	.96	.99	Moderate ALSFRS-R effect and strong survival effect:
2b	14	48	.63	.93	.87	CAFS has more power than the slope analysis, which can underestimate slope due to missing data (loss to follow-up and mortality)
3a	23	2	.98	.05	.78	Moderate ALSFRS-R effect and
3b	23	–15	.97	.12	.58	a) no survival effect:
						If the two endpoints do not show consistent results CAFS will have less power than an analysis of the slopes alone providing a composite analysis that appropriately reflects the lack of consistency of evidence for a drug effect.
						b) negative survival effect:
						CAFS avoids a false-positive trial by incorporating survival data. Slopes analysis mistakenly reports a positive trial result.
4	4	50	.09	.95	.48	No ALSFRS-R effect and strong survival effect:
						CAFS is not as powerful as the survival analysis but is more powerful than slopes analysis.

ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised; CAFS: Combined Assessment of Function and Survival.

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