Use of clinical staging in amyotrophic lateral sclerosis for phase 3 clinical trials.
OBJECTIVE
The use of clinical staging in the fatal neurodegenerative disease amyotrophic lateral sclerosis would have value in optimising future therapeutic trials. We aimed to use previous clinical trial data to determine the length of time patients spend in each of four proposed stages, its range and transition patterns to subsequent stages.


METHODS
Using databases from two multicentre clinical trials, patients were retrospectively staged through the trial course. At each stage we assessed whether patients then progressed to an earlier, consecutive or later stage or death. Duration spent in each stage before progression to a later stage was calculated.


RESULTS
There were 725 patients. No patients moved to an earlier stage. More patients at stages 1, 2 and 3 progressed to the consecutive stage rather than skipping a stage. 59.3% of patients at Stage 1 progressed to Stage 2, 54.0% of patients at Stage 2 progressed to Stage 3, 42.3% of patients at Stage 3 progressed to Stage 4 and 47.0% of Stage 4 patients progressed to death. Transition times between stages had a median duration of 3 to 7 months for stages 2 to 4.


CONCLUSIONS
We have shown using trial data that transition times between stages are short. Use of stage duration as an endpoint might allow a shorter trial duration. We have shown face validity in this system as most patients progress through consecutive stages, and none revert to earlier stages. Furthermore, we have shown the system is reliable across populations and therefore has content validity.
King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
Rubika
http://orcid.org/0000-0002-6817-2365
R
Balendra
King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
Ashley
A
Jones
Health Service and Population Research, Institute of Psychiatry, King's College London, London, UK.
Naheed
N
Jivraj
Institute of Health and Safety, Newcastle University, Newcastle Upon Tyne, UK.
I Nick
IN
Steen
Walton Centre for Neurology & Neurosurgery, Liverpool, UK.
Carolyn A
CA
Young
Academic Neurology Unit, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Pamela J
PJ
Shaw
Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.
Martin R
MR
Turner
Brighton and Sussex Medical School, Trafford Centre for Biomedical Research, University of Sussex, Falmer, East Sussex, UK.
P Nigel
PN
Leigh
King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
Ammar
A
Al-Chalabi
D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D013997:Time Factors
ALS; MOTOR NEURON DISEASE; NEUROMUSCULAR; QUALITY OF LIFE; RANDOMISED TRIALS